BK Virus Nephropathy

BK virus nephropathyBK virus nephropathy

• DNA virus that belongs to the polyomaviridae family: Polyomavirus BK Polyomavirus JC SV40 New: Polyomavirus KI, Polyomavirus WU, Polyomavirus MC

BKV infection: the virusBKV infection: the virus

Structure:The BKV genome comprises three regions:

1. the NCCR

2. the structural region coding for early T proteins

3. the late structural region encoding the viral capsid proteins (VP1-3) and agnoprotein

VirologyVirology

4 major sero/genotypes:4 major sero/genotypes: group I encodes the group I encodes the

prototype strain prototype strain Dunlop (Dun),MM, Dunlop (Dun),MM, and GS;and GS;

group II encodes the group II encodes the SB strain; SB strain;

group III encodes the group III encodes the AS strain; and AS strain; and

group IV encodes the group IV encodes the MG strains.MG strains.

5300 bp

Icosahedral,40-44 nm diam

History of BKVNHistory of BKVN

First reported in a renal transplant patient, BK, in First reported in a renal transplant patient, BK, in 1971.1971.

No reported cases of this disease for the next 24 No reported cases of this disease for the next 24 years, until Purighalla and co-workers observed years, until Purighalla and co-workers observed their first case in early 1995.their first case in early 1995.

Subsequently there has been a surge in reported Subsequently there has been a surge in reported cases worldwide.cases worldwide.

Epidemiology of BKV infectionEpidemiology of BKV infection

Approx. 80% of the general population has a Approx. 80% of the general population has a detectable antibody to BKV, which appears early detectable antibody to BKV, which appears early in life and remains elevated throughout life.in life and remains elevated throughout life.

The prevalence of BK viruria, viremia, and The prevalence of BK viruria, viremia, and nephritis after renal Tx has been estimated at 30, nephritis after renal Tx has been estimated at 30, 13, and 8%, respectively.13, and 8%, respectively.

N Engl J Med 2002; 347 : 488–496.

J Gen Virol 2003; 84: 1499–1504

Epidemiology of BKV infectionEpidemiology of BKV infection

BKVN is also seen in other SOTx but at a much lower BKVN is also seen in other SOTx but at a much lower rate. It also has been observed in patients with HIV rate. It also has been observed in patients with HIV infection, other immunodeficiency states and rarely infection, other immunodeficiency states and rarely also in SLE.also in SLE.

Primary Infection occurs in early life when it is either Primary Infection occurs in early life when it is either asymptomatic or with mild URTI. asymptomatic or with mild URTI. Thereafter BKV Thereafter BKV largely persists in the kidneys and urinary tract in a largely persists in the kidneys and urinary tract in a latent form.latent form.

TransmissionTransmission

Transmission through the feco-oral and Transmission through the feco-oral and respiratory routes has been suggestedrespiratory routes has been suggested

Other routes include blood transfusion, Other routes include blood transfusion, transplacentally, through semen, &organ transplacentally, through semen, &organ transplantationtransplantation

BKV nephropathy after kidney Tx: BKV nephropathy after kidney Tx: risk factorsrisk factors

Patient determinants

age>50 yrs diabetesnegative recipient antibody before Tx

Organ determinants

degree of HLA-matchingprior rejection episodespositive donor serostatus before Tx

Viral determinants

genome mutation and rearrangements

Immunesuppression

major risk factor for BKVN a state of “over-immunosuppression”, rather than a specific agent is responsible for an increased risk of BKVN development

Pathogenesis of BKVNPathogenesis of BKVN

Source of infectionSource of infection

Two proposed hypotheses:Two proposed hypotheses:

1.1.Transmission occurs through the donor kidney.Transmission occurs through the donor kidney.

2.2.Reactivation in the recipient renal epithelium after Reactivation in the recipient renal epithelium after transplantation.transplantation.

Immunology of BKVN: Immunology of BKVN: Humoral immunityHumoral immunity

Humoral immunity seems to be involved in the Humoral immunity seems to be involved in the regulation of BKV activity:regulation of BKV activity: Early report of fatal BKV infection with renal damage in a pt of hyper- Early report of fatal BKV infection with renal damage in a pt of hyper-

IgM immunodeficiency.IgM immunodeficiency.

In paediatric renal Tx recipients, the absence of BKV-specific anti In paediatric renal Tx recipients, the absence of BKV-specific anti bodies was associated with an increased rate of acute BKV infection.bodies was associated with an increased rate of acute BKV infection.

recovery from BKVAN and clearance of BKV was associated with the recovery from BKVAN and clearance of BKV was associated with the development of BKV-specific IgG anti bodies.development of BKV-specific IgG anti bodies.

Other studies did not show high titers were protective against Other studies did not show high titers were protective against development of BKVAN and very titer were seen in patients where the development of BKVAN and very titer were seen in patients where the BKV viruria was highest.BKV viruria was highest.

N. Engl. J. Med. 308 , 1192–1196(1983)

Am. J. Transplant. 7, 2727–2735 (2007).

Am. J. Transplant. 5, 2719–2724 (2005)

J. Clin. Virol. 43, 184–189 (2008)

Humoral immunityHumoral immunity

Taken together, the current data suggest that: Taken together, the current data suggest that:

BKV-specific antibodies provide BKV-specific antibodies provide incomplete incomplete protection protection against BKVAN for patients after kidney against BKVAN for patients after kidney transplantation. transplantation.

However, they However, they may attenuate the severity may attenuate the severity of BKV of BKV infection and its clinical manifestations. infection and its clinical manifestations.

In addition, evaluation of BKV-specific antibody In addition, evaluation of BKV-specific antibody titers can provide information on the titers can provide information on the severityseverity of of past or current BKV infections and on past or current BKV infections and on prognosis.prognosis.

Immunology of BKVN: Immunology of BKVN: Cellular immunityCellular immunity

Role of Immunosuppressive Role of Immunosuppressive medicationsmedications

Prior to 1995; when Tac and MMF were Prior to 1995; when Tac and MMF were introduced, BKVAN was a rare entity.introduced, BKVAN was a rare entity.

The occurrence of BKVN is not due to specific The occurrence of BKVN is not due to specific immunosuppressive agents, but may be related to immunosuppressive agents, but may be related to the overall degree of immunosuppression.the overall degree of immunosuppression.

TropismTropism of the virus for renal tubular cells and of the virus for renal tubular cells and their replication in these cells.their replication in these cells.

Potential pathogenetic mechanisms involved in the occurrence of BKVN from BK viremia.

timingof BKV infectiontimingof BKV infection

Fifty percent of patients who develop BK viremia Fifty percent of patients who develop BK viremia do so by 3 months after kidney transplantation.do so by 3 months after kidney transplantation.

Ninety-five percent of BKV nephropathy occurs in Ninety-five percent of BKV nephropathy occurs in the first 2 years after kidney transplantation.the first 2 years after kidney transplantation.

Clinical Features of BKV infectionClinical Features of BKV infection

Most renal transplant recipients with BKVN Most renal transplant recipients with BKVN manifest with manifest with renal dysfunctionrenal dysfunction. .

OccasionallyOccasionallyureteric obstructionureteric obstruction and and hydronephrosishydronephrosis. .

Cystitis(haemorrhagic/nonhaemorrhagic).Cystitis(haemorrhagic/nonhaemorrhagic).

Featurs of viremiaFeaturs of viremia

Rare fatal disseminated BK virus infection after Rare fatal disseminated BK virus infection after cadaveric transplantation has also been reported.cadaveric transplantation has also been reported.

Diagnosis of BKVANDiagnosis of BKVAN

Decoy cellsDecoy cells

Decoy cells are renal tubular or urothelial cells Decoy cells are renal tubular or urothelial cells with intranuclear BKV-bearing inclusion bodies.with intranuclear BKV-bearing inclusion bodies.

Problems in using Decoy cells as screening test:Problems in using Decoy cells as screening test: BKV shedding in the urine occurs in a substantial BKV shedding in the urine occurs in a substantial

proportion of healthy Individuals, only quantitative proportion of healthy Individuals, only quantitative cytology results are suitable for routine diagnostic use.cytology results are suitable for routine diagnostic use.

Urine cytology in BKV infectionUrine cytology in BKV infection

Decoy cells are seen with three methods:Decoy cells are seen with three methods: Papanicolaou stainsPapanicolaou stains Electron microscopyElectron microscopy Phase contrast microscopyPhase contrast microscopy

Nefrologia 2010;30(6):613-7

What to screen?What to screen?

Urine NAT has a very high negative predictive value Urine NAT has a very high negative predictive value and it tends to precede Plasma NAT by 4 weeks and and it tends to precede Plasma NAT by 4 weeks and histological BKVAN by 12 weeks.histological BKVAN by 12 weeks.

But it has been shown that But it has been shown that the presence of a positive the presence of a positive NAT for BKV in urine, in the absence of an elevated NAT for BKV in urine, in the absence of an elevated BKV load in the plasma, is not associated with an BKV load in the plasma, is not associated with an increased risk for BKV disease.increased risk for BKV disease.

Thus positive urine NAT requires it to be followed by a Thus positive urine NAT requires it to be followed by a plasma NAT making 2 tests necessary.plasma NAT making 2 tests necessary.

Transplantation 2005;79: 1277–1286.

Current screening guidelinesCurrent screening guidelines

Screen all kidney transplant patients for BKV Screen all kidney transplant patients for BKV using quantitative PCR of serum or plasma using quantitative PCR of serum or plasma samples at the following time points:samples at the following time points: Monthly for the first 3–6 months after transplantation, Monthly for the first 3–6 months after transplantation,

then every 3 months until the end of the first post-then every 3 months until the end of the first post-transplantation year. transplantation year.

In addition, patients should undergo PCR-based In addition, patients should undergo PCR-based screening for BKV every time an unexplained rise screening for BKV every time an unexplained rise in serum creatinine occurs, and after treatment for in serum creatinine occurs, and after treatment for acute rejection.acute rejection.

Screening testScreening test: : Decoy cells in urine, Urine DNA-Decoy cells in urine, Urine DNA-PCR for BKV, EM for BKV in urine.PCR for BKV, EM for BKV in urine.

Adjunctive test Adjunctive test (should be used within 4 weeks (should be used within 4 weeks of the screening test): BKV-DNA PCR of plasma , of the screening test): BKV-DNA PCR of plasma , VP1 mRNA in urine. Persistence of these tests for VP1 mRNA in urine. Persistence of these tests for > 3 weeks is highly suggestive.> 3 weeks is highly suggestive.

Transplantation 79: 1277–1286, 2005

biopsybiopsy

Since it has a patchy distribution Since it has a patchy distribution affecting mostly the medulla, affecting mostly the medulla, two two

core biopsy core biopsy samples including samples including medulla should be obtained.medulla should be obtained.

biopsybiopsy

BK nephropathy develops through three stagesBK nephropathy develops through three stages Stage AStage A

Few viral inclusion bodies and occasional positive Few viral inclusion bodies and occasional positive immunohistochemical staining, with an antibody to SV40 immunohistochemical staining, with an antibody to SV40 large T antigen that cross-reacts with BK large T antigenlarge T antigen that cross-reacts with BK large T antigen

Stage B Stage B Fulminant nephropathy shows an inflammatory infiltrate with Fulminant nephropathy shows an inflammatory infiltrate with

focal tubulitis, which may mimic acute rejection but includes focal tubulitis, which may mimic acute rejection but includes prominent intranuclear inclusions and T-antigen stainingprominent intranuclear inclusions and T-antigen staining

Stage C Stage C Diffuse interstitial fibrosis and closely resembles chronic Diffuse interstitial fibrosis and closely resembles chronic

allograft nephropathyallograft nephropathy

BK NephropathyBK Nephropathy

Variable degree of Variable degree of interstitial inflammation, interstitial inflammation, fibrosis, atrophyfibrosis, atrophy

Similar in appearance to Similar in appearance to cellular rejectioncellular rejection

Immunohistochemistry Immunohistochemistry usefuluseful

Nefrologia 2010;30(6):613-7

Differential diagnosisDifferential diagnosis

Early BKVN Vs acute rejectionEarly BKVN Vs acute rejection Late BKVN Vs CANLate BKVN Vs CAN

Differential diagnosisDifferential diagnosis

Nefrologia 2010;30(6):613-7

More recently..More recently..

The use of electron microscopy to detect The use of electron microscopy to detect cast-like, three dimensional polyoma virus cast-like, three dimensional polyoma virus aggregates in urine called “aggregates in urine called “Haufen” Haufen” has has been found to be sensitive and specific for been found to be sensitive and specific for BKVN. BKVN.

The positive and negative predictive values of The positive and negative predictive values of Haufen for BK polyoma virus nephropathy were Haufen for BK polyoma virus nephropathy were 97% and 100%, respectively.97% and 100%, respectively.

ManagementManagement

Two approachesTwo approaches

Timely screening and adjustment in Timely screening and adjustment in immunosuppresionimmunosuppresion

Identify patients at risk for BK infection and Identify patients at risk for BK infection and use an immunosuppressive regimen from the use an immunosuppressive regimen from the time of transplant that could be expected to time of transplant that could be expected to minimize risk.minimize risk.

BK virus infection: TreatmentBK virus infection: Treatment

Currently, Currently, Reduction of immunosuppression remains the Reduction of immunosuppression remains the

most widely accepted approach to treatmentmost widely accepted approach to treatment

It is now assumed thatIt is now assumed that Screening all transplant patients with serial Screening all transplant patients with serial

PCR analyses of urine or serum, with PCR analyses of urine or serum, with Prompt reduction of immunosuppression when Prompt reduction of immunosuppression when

patients initially display viruria or viremia, will patients initially display viruria or viremia, will Prevent or reduce the risk for developing BKVNPrevent or reduce the risk for developing BKVN

Transplantation Reviews 2010 ;24: 28–31

Reduction in immunosuppresionReduction in immunosuppresion

The most robust evidence supportsThe most robust evidence supports Switch Switch

Tacrolimus to CsA (trough level 100–150 ng/mL)Tacrolimus to CsA (trough level 100–150 ng/mL) CsA/MMF to CsA/ steroids or tacrolimus/steroidsCsA/MMF to CsA/ steroids or tacrolimus/steroids

Decrease Decrease Tacrolimus trough level to less than 6 ng/mLTacrolimus trough level to less than 6 ng/mL MMF dose to less than or equal to 1g/dMMF dose to less than or equal to 1g/d CsA trough level to 100 to 150 ng/mLCsA trough level to 100 to 150 ng/mL

Conversion from MMF to an mTORinhibitorConversion from MMF to an mTORinhibitor

Adjunctive TreatmentAdjunctive Treatment

Antiviral agents used empirically for BKVN Antiviral agents used empirically for BKVN include include

CidofovirCidofovir Leflunomide,Leflunomide, Quinolone antibiotics, and Quinolone antibiotics, and Intravenous immunoglobulinIntravenous immunoglobulin

True efficacy of these strategies is unclear True efficacy of these strategies is unclear because because No randomized control trials have been done, and the No randomized control trials have been done, and the Value of therapy independent of reduction of Value of therapy independent of reduction of

immunosuppression has not been specifically immunosuppression has not been specifically evaluatedevaluated

Transplantation Reviews 2007;21:77–85

Adjunctive therapiesAdjunctive therapies

Quinolone antibioticsQuinolone antibiotics: may have anti-BK virus : may have anti-BK virus properties by inhibiting DNA topoisomerase properties by inhibiting DNA topoisomerase activity and SV40 large T antigen helicase.activity and SV40 large T antigen helicase.

IVIG:IVIG: in doses of 500mg/kg have been used. in doses of 500mg/kg have been used.

Adjunctive therapiesAdjunctive therapies

Leflunomide:Leflunomide: is a prodrug whose anti-metabolite, is a prodrug whose anti-metabolite, A77 1726, has both immunosuppressive and anti-A77 1726, has both immunosuppressive and anti-viral activity.viral activity. Dosage: 100mg/d X 5 days followed by Dosage: 100mg/d X 5 days followed by 20–60 mg daily, 20–60 mg daily,

with a target trough blood level of 50–100 mg/mlwith a target trough blood level of 50–100 mg/ml

Cidofovir:Cidofovir: a nucleotide analogue of cytosine that a nucleotide analogue of cytosine that is active against various DNA viruses. is active against various DNA viruses. Dosage: 0.25-0.33mg/kg/dose X 1-3 doses every 2-3 Dosage: 0.25-0.33mg/kg/dose X 1-3 doses every 2-3

weeksweeks Problem with cidofovir is that it is nephrotoxic.Problem with cidofovir is that it is nephrotoxic.

BK virus infection: TreatmentBK virus infection: Treatment

Recent review “Treatment of polyomavirus Recent review “Treatment of polyomavirus infection in kidney transplant recipients” infection in kidney transplant recipients” ConclusionsConclusions There does not seem to be a graft survival There does not seem to be a graft survival

benefit of adding cidofovir or leflunomide to benefit of adding cidofovir or leflunomide to immunosuppression reduction for the immunosuppression reduction for the management of PVANmanagement of PVAN

Evidence base is poor and highlights the Evidence base is poor and highlights the urgent need for adequately powered urgent need for adequately powered randomized trials to define the optimal randomized trials to define the optimal treatment of this important conditiontreatment of this important condition

Transplantation. 2010 May 15;89(9):1057-70.

RetransplantationRetransplantation

It is a medical and an ethical dilemma It is a medical and an ethical dilemma Whether retransplantation should be done after Whether retransplantation should be done after

a patient loses the renal graft to polyoma a patient loses the renal graft to polyoma nephropathynephropathy

Should immunosuppressive therapy be altered? Should immunosuppressive therapy be altered? Is nephroureterectomy of the failed graft Is nephroureterectomy of the failed graft

necessary? necessary? What is the natural course of the disease after What is the natural course of the disease after

retransplantation? retransplantation?



Retransplantation after polyomavirus- associated Retransplantation after polyomavirus- associated nephropathy has been reported in 17 casesnephropathy has been reported in 17 cases

In these cases, recurrence of nephropathy has In these cases, recurrence of nephropathy has occurred in 2 patients and viremia alone in a occurred in 2 patients and viremia alone in a third patient.third patient.

For most of these patients, immunosuppression For most of these patients, immunosuppression after retransplantation was the same as for the after retransplantation was the same as for the first transplantationfirst transplantation Allograft nephrectomy was performed in 11 of the 15 Allograft nephrectomy was performed in 11 of the 15

patientspatients



Also, all 15 patients had reconstituted their Also, all 15 patients had reconstituted their BKV-specific immune control, as BKV-specific immune control, as demonstrated by negative urine cytology demonstrated by negative urine cytology pretransplantpretransplant

Authors conclude that Authors conclude that Retransplantation in patients without active Retransplantation in patients without active

replication is generally safereplication is generally safe



Authors conclude that..Authors conclude that.. Control of viral replication, allowing enough Control of viral replication, allowing enough

time to raise sufficient immune response, time to raise sufficient immune response, which usually requires more than 12 weeks of which usually requires more than 12 weeks of reduced immunosuppression, appears to be a reduced immunosuppression, appears to be a desirable goal before a second transplant is desirable goal before a second transplant is contemplated.contemplated.

In addition, nephroureterectomy is not In addition, nephroureterectomy is not necessary when viral replication is absent necessary when viral replication is absent before retransplantation.before retransplantation.


Take home pearlsTake home pearls

significant concern in kidney transplant significant concern in kidney transplant patientspatients

Intensive viral monitoring and adjustment Intensive viral monitoring and adjustment of immunosuppressionof immunosuppression

do not have reliable antiviral drugs do not have reliable antiviral drugs available at this timeavailable at this time

Differentiation from rejection challengingDifferentiation from rejection challenging

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BK Virus Nephropathy

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