1. Vishal Golay 09/03/2012Sources: Nat. Rev. Nephrol. 7, 399406 (2011) Clin J Am Soc Nephrol 2: S36 S46, 2007 Nephrol Dial Transplant (2006) 21: 33643367

2. Family Polyomaviridae HumansAnimalsJC virus BK virusMurine Simian(SV 40) 3. 4 major sero/genotypes: group I encodes theprototype strainDunlop (Dun),MM,and GS; group II encodes theSB strain;5300 bp group III encodes theAS strain; and group IV encodes theMG strains.Icosahedral,40-44 nm diam 4. First reported in a renal transplant patient, BK, in1971. No reported cases of this disease for the next 24years, until Purighalla and co-workers observedtheir first case in early 1995. Subsequently there has been a surge in reportedcases worldwide. 5. Approx. 80% of the general population has adetectable antibody to BKV, which appears early inlife and remains elevated throughout life. J Gen Virol 2003; 84: 14991504 The prevalence of this virus in the ESRDpopulation, kidney donors, and transplantrecipients has not been well defined. The prevalence of BK viruria, viremia, andnephritis after renal Tx has been estimated at 30,13, and 8%, respectively. N Engl J Med 2002; 347 : 488496. 6. BKVN is also seen in other SOTx but at a much lowerrate. It also has been observed in patients with HIVinfection, other immunodeficiency states and rarelyalso in SLE. Primary Infection occurs in early life when it is eitherasymptomatic or with mild URTI. Thereafter BKVlargely persists in the kidneys and urinary tract in alatent form. The principal routes of transmission are fecal-oral,respiratory, transplacental, or from donor tissue. 7. source of BKVimmunological Hypotheticalrenalaspects mechanismsspecificity viralvirulence 8. Two proposed hypotheses:1. Transmission occurs through the donor kidney.2. Reactivation in the recipient renal epithelium after transplantation. 9. Humoral immunity seems to be involved in theregulation of BKV activity: Early report of fatal BKV infection with renal damage in a pt ofhyper- IgM immunodeficiency. N. Engl. J. Med. 308 , 11921196(1983) In paediatric renal Tx recipients, the absence of BKV-specific antibodies was associated with an increased rate of acute BKVinfection.Am. J. Transplant. 7, 27272735 (2007). recovery from BKVAN and clearance of BKV was associated withthe development of BKV-specific IgG anti bodies.Am. J. Transplant. 5, 27192724(2005) Other studies did not show high titers were protective againstdevelopment of BKVAN and very titer were seen in patientswhere the BKV viruria was highest. J. Clin. Virol. 43, 184189 (2008) 10. Taken together, the current data suggest that: BKV-specific antibodies provide incompleteprotection against BKVAN for patients after kidneytransplantation. However, they may attenuate the severity of BKVinfection and its clinical manifestations. In addition, evaluation of BKV-specific antibodytiters can provide information on the severity ofpast or current BKV infections and on prognosis. 11. Prior to 1995; when Tac and MMF wereintroduced, BKVAN was a rare entity. Reduction or pre-emptive withdrawal ofimmunosuppressive medication was associatedwith BKV clearance. The occurrence of BKVN is not due to specificimmunosuppressive agents, but may be related tothe overall degree of immunosuppression. 12. Tropism of the virus for renal tubular cells and theirreplication in these cells. Higher virulence acquired by BKV can contribute. HLA mismatch between the donor and recipient. Age >50yrs, male gender and diabetes have alsobeen found to have increased risk. 13. Potential pathogenetic mechanisms involved in theoccurrence of BKVN from BK viremia. 14. Fifty percent of patients who develop BK viremiado so by 3 months after kidney transplantation. Ninety-five percent of BKV nephropathy occurs inthe first 2 years after kidney transplantation. 15. Most renal transplant recipients with BKVN manifestwith renal dysfunction. Progressive renal failure hasbeen reported in approximately 3060% of cases. Occasionally, subjects can also present with uretericobstruction and hydronephrosis. Cases of cystitishave been reported. Routine post-transplant protocol biopsy has alsodetected BKVN in the absence of serum creatinineelevation. Rare fatal disseminated BK virus infection aftercadaveric transplantation has also been reported. 16. Diagnosis of BKVAN 17. Documentation ofDemonstration of viral cytopathic the virus itselfeffectsDiagnosis ofBKV infectionDemonstration ofHistologic findingsimmunity to virus 18. Enlarged nucleus (Ground-glass appearance). Chromatin margination. Irregular chromatin pattern. Multiple nuclear inclusion bodies of various shapesand sizes. Single nuclear inclusion body with a bird-eyeappearance. Intracytoplasmic vacuoles and vacuolatedcytoplasm(rare) 19. Decoy cells are renal tubular or urothelial cells withintranuclear BKV-bearing inclusion bodies. Problems in using Decoy cells as screening test: BKV shedding in the urine occurs in a substantialproportion of healthy Individuals, only quantitativecytology results are suitable for routine diagnostic use. It cannot distinguish between different types ofpolyomaviruses. Special skills are required for the detection of decoycells, which limit its application. 20. Decoy cells are seen with three methods: Papanicolaou stains Electron microscopy Phase contrast microscopy 21. Urine NAT has a very high negative predictive valueand it tends to precede Plasma NAT by 4 weeks andhistological BKVAN by 12 weeks. But it has been shown that the presence of apositive NAT for BKV in urine, in the absence of anelevated BKV load in the plasma, is not associatedwith an increased risk for BKV disease. Thus positive urine NAT requires it to be followed bya plasma NAT making 2 tests necessary. Transplantation 2005;79: 12771286. 22. Screen all kidney transplant patients for BKV usingquantitative PCR of serum or plasma samples atthe following time points: Monthly for the first 36 months after transplantation,then every 3 months until the end of the first post-transplantation year. In addition, patients should undergo PCR-basedscreening for BKV every time an unexplained risein serum creatinine occurs, and after treatment foracute rejection. 23. Screening test: Decoy cells in urine, Urine DNA-PCR for BKV, EM for BKV in urine. Adjunctive test (should be used within 4 weeks ofthe screening test): BKV-DNA PCR of plasma orurine, VP1 mRNA in urine. Persistence of thesetests for > 3 weeks is highly suggestive.Transplantation 79: 12771286, 2005 24. Renal biopsy is the gold standard in the diagnosis of BKVAN. Skip lesions can cause false negative results (up to 36.5%) andtherefore two cores containing medullary tissue should be examined. The diagnostic accuracy of histological screening for BKVAN can beimproved by IHC, in situ nucleic acid hybridization, and EM. 25. Approximately 4060% of renal grafts with BKVNdevelop progressive graft loss. 26. Treatment of BKVAN 27. The most importantcomponent of managementof BKVAN is a decrease inimmunosuppression. Most centers withdraw theanti-metabolite and decreaseCNI to the lowest possibledose. Am J Transplant 5: 582594, 2005 28. Transplantation 2005;79: 12771286 29. Quinolone antibiotics: may have anti-BK virusproperties by inhibiting DNA topoisomerase activityand SV40 large T antigen helicase. IVIG: in doses of 500mg/kg have been used. Theadditional advantage of IVIG is that it is also usedfor Rx of rejection. 30. Leflunomide: is a prodrug whose anti-metabolite,A77 1726, has both immunosuppressive and anti-viral activity. Dosage: 100mg/d X 5 days followed by 2060 mg daily,with a target trough blood level of 50100 mg/ml Cidofovir: a nucleotide analogue of cytosine thatis active against various DNA viruses. Dosage: 0.25-0.33mg/kg/dose X 1-3 doses every 2-3weeks Problem with cidofovir is that it is nephrotoxic. 31. In a retrospective data from UNOS of 2,061 recipientsof RTx, only the reduction of immunosuppression wasnot associated with a high risk of graft failure. Otheradjunctive therapies were not found useful.Am. J. Transplant. 9 (Suppl. 2), 275 (2009)Another meta-analysis published in 2010 evaluated555 different papers on outcomes of BKV therapy. Theresearchers concluded that patients treated withadjuvant therapy (in particular cidofovir andleflunomide) demonstrated no improvement in graftsurvival in comparison to patients treated with areduction of immunosuppressive therapy Transplantation 89, 10571070 (2010). 32. Retransplantation remains a viable option forpatients developing graft loss after BKVAN. In a review in 2005, PVAN recurred in 15% ofretransplantations compared with 5% of primarytransplantations Transplantation 2005;79: 12771286 Dharnidharka et al. showed that the outcome in126 re-Txs was almost similar to controls withoutBKVAN with respect to outcomes as well asimmunosuppression.Am J Transplant. 2010;10(5):1312. 33. BKV infection is very common and this limits theimprovement in transplantation outcomes. Screening and early detection of infection isnecessary to initiate pre-emptive measures. Reduction of immunosuppression remains the onlyvalidated measures for treatment. This approach is tricky due to the risk of rejection. 34. THANK YOU