2 bk virus infection post renal transplant

Post renal transplant BK virus Post renal transplant BK virus infectioninfection

Dr. Sunil Kumar Daksh Parajapati Dr. Sunil Kumar Daksh Parajapati

IntroductionIntroduction

We will discuss todayWe will discuss today Polyoma virus infection, replication, and Polyoma virus infection, replication, and

disease in renal transplant recipientsdisease in renal transplant recipients Treatment of PVAN (Polyoma virus Treatment of PVAN (Polyoma virus

associated nephropathy)associated nephropathy)

Polyoma virusPolyoma virus

Five known human polyoma virusesFive known human polyoma viruses BK & JC virusBK & JC virus KI virus (KIPyV) & WU viruses (WUPyV) KI virus (KIPyV) & WU viruses (WUPyV)

were identified in 2007 from respiratory were identified in 2007 from respiratory secretions of a RTI pt.secretions of a RTI pt. KI & WU viruses are named after the institutionsKI & WU viruses are named after the institutions

In Jan 2008, Feng et al., identified Merkel cell In Jan 2008, Feng et al., identified Merkel cell polyoma virus (MCPyV) was a/w Merkel cell polyoma virus (MCPyV) was a/w Merkel cell carcinomacarcinoma

TransmissionTransmission

Occurs mostly through close contactOccurs mostly through close contact 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

BK virus infectionBK virus infection

Named after the first patient in which it was Named after the first patient in which it was described by Gardner described by Gardner (Sudanese kidney transplant patient with ureteric stenosis whose initials were BK)

Ubiquitous polyomavirusUbiquitous polyomavirus Acquired in childhood and becomes latent in Acquired in childhood and becomes latent in

uroepithelial cellsuroepithelial cells Reactivation of BK virus occurs in patients in Reactivation of BK virus occurs in patients in

immunosuppressed states, including immunosuppressed states, including After transplantationAfter transplantation HIVHIV

Transplantation Proceedings 2008; 40: S48–51

BK virus infectionBK virus infection

Typically occurs during childhood, with Typically occurs during childhood, with seroprevalence rates of 65% to 90% by the seroprevalence rates of 65% to 90% by the age of 10 years, and is usually asymptomaticage of 10 years, and is usually asymptomatic

Individuals with altered immunity, however, Individuals with altered immunity, however, can experience high-level replication and may can experience high-level replication and may present with urine cytology (“decoy” cells)present with urine cytology (“decoy” cells)

Transplantation Reviews 2008;22:241–51

Nefrologia 2010;30(6):613-7

Polyomavirus (BK)–associated Polyomavirus (BK)–associated nephropathy (BKVN) nephropathy (BKVN)

Polyomavirus (BK)–associated Polyomavirus (BK)–associated nephropathy (BKVN) nephropathy (BKVN) Now recognized as significant problem in Now recognized as significant problem in

renal transplants that may lead to progressive renal transplants that may lead to progressive allograft dysfunctionallograft dysfunction

First recognized in 1971 in adult renal First recognized in 1971 in adult renal transplant recipientstransplant recipients

Clinical manifestationsClinical manifestations

Risk factors:Risk factors: Older, male, White, diabetic recipientOlder, male, White, diabetic recipient More HLA mm, ACR, DGFMore HLA mm, ACR, DGF Net state of immune suppressionNet state of immune suppression Seronegativity of the recipientSeronegativity of the recipient lack of HLA-C7 lack of HLA-C7 deceased donor transplantationdeceased donor transplantation

Asymptomatic allograft dysfunctionAsymptomatic allograft dysfunction Prior tubular injury from rejection or drugs, surgical injury, warm Prior tubular injury from rejection or drugs, surgical injury, warm

ischemia & reperfusion injuryischemia & reperfusion injury Suspect BK when rejection does not resolve with Suspect BK when rejection does not resolve with

usual therapyusual therapy

Polyomavirus infectionPolyomavirus infection

In renal transplant recipients, In renal transplant recipients, Polyomavirus-associated nephropathy Polyomavirus-associated nephropathy

(PVAN) develops in 5% of patients and leads (PVAN) develops in 5% of patients and leads to graft loss in approximately 50% of casesto graft loss in approximately 50% of cases

Pathogenesis of PVAN characterized byPathogenesis of PVAN characterized by Persisting high-level polyoma BK virus (BKV) Persisting high-level polyoma BK virus (BKV)

replication in renal tubular epithelial cells, replication in renal tubular epithelial cells, inflammation, and progressive organ failure with inflammation, and progressive organ failure with tubular atrophy and fibrosistubular atrophy and fibrosis


BK virus NephropathyBK virus Nephropathy

Polyoma virus: Renal transplant recipientsPolyoma virus: Renal transplant recipients Most cases of BKN occur within the first year Most cases of BKN occur within the first year

after kidney transplantationafter kidney transplantation Definitive diagnosis requires histopathological Definitive diagnosis requires histopathological

assessment, notably to exclude acute assessment, notably to exclude acute rejectionrejection


BK virus NephropathyBK virus Nephropathy

BK viruria: 20% - 40% of renal transplant BK viruria: 20% - 40% of renal transplant patients patients

BK viremia: approx. 12% of patientsBK viremia: approx. 12% of patients Studies have indicated thatStudies have indicated that

BK viremia greater than 10eBK viremia greater than 10e44/mL is predictive of /mL is predictive of definitive PVAN, and these patients should be definitive PVAN, and these patients should be regarded as having “presumptive PVAN,” and regarded as having “presumptive PVAN,” and

Reduced immunosuppression should be Reduced immunosuppression should be consideredconsidered


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

Since it has a patchy distribution affecting Since it has a patchy distribution affecting mostly the medulla, two core biopsy mostly the medulla, two core biopsy samples including medulla should be samples including medulla should be

obtained.obtained.

Polyomavirus infectionPolyomavirus infection

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

ManagementManagement

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 “Haufen” has aggregates in urine called “Haufen” 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.

BK virus infection: TreatmentBK virus infection: Treatment

The treatment of BKVN is unlikely to be The treatment of BKVN is unlikely to be satisfactory until safe and effective satisfactory until safe and effective antiviral drugs are discoveredantiviral drugs are discovered Hence, there is a lot of current emphasis on Hence, there is a lot of current emphasis on

the prevention of this distressing complicationthe prevention of this distressing complication


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



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

However, the evidence base is poor and However, the evidence base is poor and highlights the urgent need for adequately highlights the urgent need for adequately powered randomized trials to define the powered randomized trials to define the optimal treatment of this important conditionoptimal treatment of this important condition

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


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 mTORinhibitor or Conversion from MMF to an mTORinhibitor or from tacrolimus/MMF to sirolimus/steroids is also from tacrolimus/MMF to sirolimus/steroids is also an option, but with fewer supportive data.an option, but with fewer supportive data.

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.


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.


ConclusionsConclusions

BKV infections remain a significant concern in BKV infections remain a significant concern in kidney transplant patientskidney transplant patients

Intensive viral monitoring and preemptive Intensive viral monitoring and preemptive adjustment of immunosuppression have led to adjustment of immunosuppression have led to reduction in the incidence of overt viral nephropathyreduction in the incidence of overt viral nephropathy

Nonetheless, approximately 30% of patients in Nonetheless, approximately 30% of patients in major transplant programs develop viruria and need major transplant programs develop viruria and need to be carefully monitored for the possible to be carefully monitored for the possible development of this complicationdevelopment of this complication


In those patients who do develop BK Virus In those patients who do develop BK Virus induced allograft injury, we do not have reliable induced allograft injury, we do not have reliable antiviral drugs available at this timeantiviral drugs available at this time

Although early diagnosis and prompt therapeutic Although early diagnosis and prompt therapeutic intervention have reduced rates of overt graft intervention have reduced rates of overt graft loss to approximately 15%, surviving grafts loss to approximately 15%, surviving grafts frequently show progressive decline in graft frequently show progressive decline in graft functionfunction


It is likely that long-term low-grade viruria and It is likely that long-term low-grade viruria and viremia promote the development of chronic viremia promote the development of chronic allograft nephropathyallograft nephropathy

The magnitude of this problem needs to be The magnitude of this problem needs to be clarified by future clinical studies.clarified by future clinical studies.

THANK YOUTHANK YOU

2 bk virus infection post renal transplant

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