BK virus nephropathy


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1 : BKV associated nephropathy 13/07/2011
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3 : Bk virus nephropathy Introduction Virology Epidemiology Pathogenesis Clinical presentations Management Recent trends Prevention/preemptive strategies Summary
4 : Introduction-bk virus nephropathy BKV was first isolated in 1970 from a Sudanese kidney transplantation recipient with a ureteric stricture. Epidemiological studies showed that up to 90% of some human populations become exposed to BKV by adulthood . Randhawa PS, Vats A, Shapiro R et al. BK virus: Discovery, epidemiology, and biology. Graft 2002; 2 (Suppl 5): S19–S27
5 : Introduction-bk virus nephropathy After kidney transplantation, 10–60% of patients were noted to excrete virus in the urine. However, viruria was typically asymptomatic or associated with only transient graft dysfunction, though occasionally, virus-induced tissue damage was noted at allograft nephrectomy or at autopsy.
6 : Introduction-bk virus nephropathy A new era in the study of BKV began when BKV nephropathy (BKVN) was diagnosed by a needle biopsy in a renal transplant recipient suspected of having acute rejection. This case was diagnosed in 1993 at Pittsburgh and published in 1996; In the following years, additional cases were reported from kidney transplant centers worldwide. It is commonly believed that the epidemic of BKVN in the 1990s is the result of potent immunosuppressive drugs such as tacrolimus, mycophenolate mofetil and sirolimus.
7 : Immunosuppression is the main risk factor for BKV reactivation 0 100 90 80 70 60 50 40 30 20 10 Percentage (%) 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 Rejection < 12 month 1 year allograft survival Radiation Prednisone 6MP Azathioprine At Gam BKV CYA OKT3 ATG/ALG CYA ME FK506 MMF DACLIZUMAB BASILOGMAB THYMOGLOBIN SIROLIMUS FTY720 CAMPATH IH EVEROLIMUS BILATACEPT EFALIZUMAB
8 : virology Polyomavirus BK virus (BKV) is a double-stranded DNA virus with a 5-kb genome. It has been classified in the Polyomaviridae family, which includes JC virus (JCV), a well known cause of progressive multifocal leukoencephalopathy, and the simian virus SV40 . The BKV genome comprises the non-coding control region (NCCR), the early-coding region coding for the small and large T antigens, the late-coding region coding for the viral capsid proteins (VP1, VP2 and VP3) and agnoprotein.
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10 : DNA virus that belongs to the polyomaviridae family: Polyomavirus BK Polyomavirus JC SV40 New: Polyomavirus KI, Polyomavirus WU, Polyomavirus MC BKV 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
11 : virology The NCCR contains (a) the origin of replication (ori) and (b) the regulatory regions containing enhancer elements that can alter viral transcription. T antigen binds to tumor suppressor proteins Rb and p53 and initiates the cell cycle in host cells.
12 : virology VP1, VP2 and VP3 are structural proteins that make up the viral capsid. The VP1 gene displays considerable genetic heterogeneity, and this genetic variation has led to recognition of viral genotypes I, II, III and IV. Agnoprotein plays a role in several cellular processes, including cell cycle progression, DNA repair, viral capsid assembly and virion release from cell.
13 : Epidemiology and pathogenesis 1:Prevalence .Primary BK infection generally occurs in childhood without specific symptoms + 90% are seropositive by 10 years 1-5% of kidney transplant patients are affected 2:Transmission Presumably transmitted via respiratory droplets Other speculated modes include urine, semen, blood transfusion and organ transplantation
14 : Epidemiology and pathogenesis Source/route of infection  immunological aspects such as host humoral and cellular immunity, alloimmune activation and immunosuppression medications; Entry into cell Renal specificity such as tropism and ischemic injury; viral virulence.
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16 : Source/routes Many different routes for the transmission of BK virus have been hypothesized. According to many authors, respiratory transmission is the most likely route ; Sexual transmission has been proposed; Monini et al. detected BKvirus in 57% of specimens of genital tissues and 95% of sperm samples. Because primary infection generally occurs before the age of sexual activity, this hypothesis would assume a sexually transmitted trigger for reactivation of BK disease; Other modes can be considered for BK viral transmission, including via urine and blood
17 : Epidemiology A ?nal proposed mechanism of transmission is transplacental passage of BK virus. This mechanism was postulated soon after the discovery of BK virus, although further studies were unable to demonstrate isolation of BK virus from specimens of either maternal or fetal tissues ; It was Pietropaolo et al. who demonstrated the presence of BK viral DNA in a high proportion of aborted fetuses and in the products of normal pregnancies
18 : Source in allograft ?Donor ?Reactivation ?Both Donor-pretransplant donor and recipient BKV-specific antibody correlated to the occurrence of post-transplant infection. However, the majority of adult renal transplant recipients have been exposed to this infection prior to transplantation.   Occurrence of BKVN has also been noted in recipients who have had pre-transplant bilateral native nephrectomy
19 : Epidemiology After primary infection, renal tubular epithelial cells and the urothelial cell layer represent the principal sites of viral latency or replication. BKV disease is rare, and almost invariably associated with an immunodeficiency status.
20 : Immunology To date, the intensity of immunosuppression has been implicated in causing BKVN with minimal attention to the host immunity. From other viral infections, it is clear that natural killer cells of the immune system offer antiviral cytotoxic activity. Adaptive immune responses follow with CD8-positive cytotoxic T cells. CD4-positive T cells boost antibody production with macrophage and augment viral clearance. Thus, host humoral and cellular immunity may play a major role in the pathogenesis of BKVN.
21 : Immunology Humoral CMI Recipients with prior immunity to BKV and circulating viral copies may not develop nephritis, as opposed to those with deficient humoral immunity. Recipient Seronegativity-severe disease IFN GAMMA CORRELATES Subjects with elevated BKV-specific IgG can still develop BKVN, suggesting the possible role of defective cellular immunity. Subjects with elevated BKV-specific IgG can still develop BKVN, suggesting the possible role of defective cellular immunity.
22 : Humoral immunity In adults, Shah reported that seropositive donors and seronegative recipients (BKV D+/R-) developed a serologically defined BKV infection most frequently (43%). Bohl et al.  found that seropositive donor and recipients (BKV D+/R+) developed BKV viruria most frequently (50%). In both studies, only 10% of seronegative donors and recipients developed BKV infection. Thus, BKV antibodies may play a role in the immune response, but they also may indicate a risk for reactivation.
23 : CMI Comoli et al.  found that despite persistently elevated BKV antibody titers, recurrent BKV viremia was associated with a low frequency of IFN-?–producing cells. Chen et al found that viremia and an elevated creatinine persisted in most recipients who had BKV nephropathy and developed high BKV antibody titers but weak cytotoxic T lymphocyte responses. However, in recipients with a strong cytotoxic T lymphocyte response but low antibody titers, viremia cleared and creatinine returned to the pre-BKV nephropathy baseline.
24 : Immunology The cellular immune response may also contribute to allograft dysfunction. Mannon et al.  found that the RNA transcriptional profiles that were associated with BKV nephropathy indicated a more intense CD8 functional response and more profibrotic response than acute cellular rejection. Hammer et al.  found that recipients with viral loads >250,000 copies/ml had detectable BKV-specific CD4+ T cells in peripheral blood, but only the two recipients with BKV-specific CD8+ T cells >0.1% lost their allografts.
25 : CMI The specificity of the cellular response may also be detrimental. Recipients with greater donor and recipient HLA mismatching had an increased incidence of BKV nephropathy, possibly mediated by more episodes of rejection, intense immunosuppression, and impaired cytotoxicity in an allogeneic environment but less allograft loss . This suggests that lysis of allogeneic BKV-infected target cells is less efficient with HLA-unrestricted T cells than with HLA-restricted T cells. T cells recognize epitopes that are shared by JCV and BKV that may produce a cross-protective effect .
26 : Immunology Occurrence of BKVN in renal transplant recipients, as opposed to heart and liver transplant subjects, unveils the role of alloimmune activation with BKV activation and subsequent frank nephritis. Investigators from Emory University have explored the role of immune activation in a mouse transplant model, and have documented that viral nephritis occurs only in the presence of alloimmune activation.40  Thus, subclinical alloimmune activation in renal graft may trigger BKV replication and nephritis.
27 : Immunology This also explains why this infection occurs in renal grafts only, as opposed to other solid organ transplant recipients. However, alloimmune activation is usually a result of suboptimal immunosuppression that contradicts BKVN therapy, which is a reduction in immunosuppressive therapy.
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29 : Impaired immune suppression balance. Bohl D L , Brennan D C CJASN 2007;2:S36-S46 ©2007 by American Society of Nephrology
30 : Immunology If cellular immunity is restored at an early stage by a reduction in immunosuppressive therapy, progression of BKV infection and the development of BKVAN are prevented. By contrast, if the T-cell-mediated immune response fails to achieve viral clearance, intragraft inflammation persists and initiates a vicious circle of increased T-cell homing, graft damage and persistent viral replication, culminating in BKVAN and, potentially, graft loss. The reduction of immunosuppression in these patients might do more harm than good, and immunomodulatory therapy should be used instead..
31 : Immunology BKV, which infects renal tubular cells, is most commonly seen in renal transplant recipients, as opposed to other immunosuppressed individuals and other solid organ transplant recipients. Renal tubular cells The precise sites of activation of BKV and mechanisms through which BKV infects renal tubular epithelial cells in transplant recipients are unknown. In animal models, viral replication during the acute phase of infection is seen in pulmonary, systemic vascular endothelial cells, and in spleenic lymphoid cells. However, viral nucleic acids are seen in renal tubular epithelial cells at 2 months and the virus itself after 6 months, which remains the major site of viral persistence
32 : BKV genomic heterogeneity has been described in systemic lupus erythematosus and bone marrow transplant recipients, as well as in healthy donors. The reported rates of mutation differ in these reports and may be correlated with changes in disease status.  It is plausible that specific BKV types may have altered virulence, or changing genomic sequence may be associated with the occurrence of nephritis or a more severe form of the disease.
33 : The NCCR shows a high degree of sequence variability. In the report, Rhandawa et al. sequenced the NCCR in 26 paraffin-embedded biopsies from 15 patients with BKV nephritis and compared them to the archetype WW strain. Their results demonstrated that there is an extensive natural variation in the viral sequence between patients However, an analysis on NCCR sequence variations did not reveal any rearrangement pattern in five subjects with nephritis. Thus, the role of molecular characterization at the DNA sequence level still needs to be explored.
34 : Proposed life cycle of BK virus as applicable to human disease. Reploeg M D et al. Clin Infect Dis. 2001;33:191-202 © 2001 by the Infectious Diseases Society of America
35 : BKV replication is common in the renal transplant population BK-PyVAN a,3 Infected tubular epithelial cells b,3 decoy cells in urine c,3 BK-PyVAN 1-10% 1,2 BK viraemia ~ 10-20% 2 BK viruria 30-50% 2 BK Seropositive 80-90% 2,3 a anti-large T-antigen staining with mouse monoclonal antibody with 3-amino-9-ethylcarbazole as chromogen and haemotoxylin as counter stain; BKV, BK virus; BK-PyVAN, BK polyoma virus-associated nephropathy 1. Egli A et al J Infect Dis 2009; 199: 837-46 2. Hirsch HH et al N Engl J Med 2009 3. Nickeleit V et al N Engl J Med 2000 342; 1309-15
36 : Immunology Many authors have reported that BK virus can exist in a latent phase in various organs . Much of the data are based on PCR experiments; exceptions are mentioned below. Similar in concept to the latent state of the herpesvirus , these authors propose that BK virus can remain within a cell in a nonreplicating or minimally replicating form. Within the cell, the latent viral genome may either remain episomal or it may be integrated in the host cell genome
37 : Immunology The kidney is the most common reported site of latent infection ; This has been demonstrated by means of both immunohistochemistry (IHC) and ISH . The second most common reported site of latent infection is the brain
38 : Immunology Reactivation disease is observed in patients with relative or absolute immunode?ciency (generally cellular immunode?ciency rather than humoral immunode?ciency), which is made evident by the increased frequency of reactivation disease in HIV-infected patients and patients who have received organ transplants
39 : Immunology States of mild immune impairment can lead to increased virus replication and the presence of the virus in urine; This phenomenon occurs, for example, in pregnant women , patients with diabetes and Elderly patients;
40 : Pathogenesis BK virus – pathogenesis Lysis of the tubular cells releases BKV into tubules with bare BM Virus particles can thus leak into intestitium, from where the virus gains access to capillaries, resulting in viremia Somewhere along this pathway, genotype rearrangements may change the virulence characteristics of the virus.
41 : Cell entry BKV interactions with host cellular receptors have been the subject of only limited investigations. The primary receptor binding determinant on BKV is the VP1 protein. The host cell receptor for BKV appears to be an N-linked glycoprotein, in which GT1b and GD1b have been identified as component gangliosides . Both these gangliosides have an a-(2-8) linked di-sialic acid-motif as a common feature
42 : Cell entry Electron microscopic observations on human biopsy material show that BKV entry into host cells is similar to SV40, and mediated by non-clathrin coated vesicles resembling caveolae. In contrast, JCV enters the cell by clathrin-dependent endocytosis. The mechanisms of endocytosis and intra-cellular trafficking utilized by BKV have not been investigated in detail.
43 : Cell entry However, it has been established that the route from cell membrane to the nucleus includes the endoplasmic reticulum and microtubules. There may also be participation of the Golgi apparatus, and other cytoskeletal elements such as actin, and microfilaments, as has been shown for other members of the polyomavirus family.
44 : Nuclear entry The mechanism by which polyomavirus traverses the nuclear envelope to enter the nucleus is only partially understood. VP2 and VP3 contain a nuclear transport signal that may facilitate nuclear targeting of the viral mini-chromosome. Nucleoporin, a protein associated with the nuclear pore complex, has also been implicated. The uncoating process of polyomaviruses has been stated to occur after the virions have entered the cell nuclei, but it has been shown for SV40 virus that some disassembly can occur in the endoplasmic reticulum
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46 : What are the risk factors for BKV replication? 1. Schold JD et al Transpl Int 2009; 22: 626-34 2. Dharnidharka VR et al Transplantation 2009; 87: 1019-26 3. Hirsch HH et al N Engl J M 2009; 86-96 4. Bohl DL, Brennan DC. Clin J Am Soc Nephrol 2007; 2(Suppl 1): S36-46 5. Brennan DC et al Am J Translant 2005; 5:582-94 CsA, cyclosporine; HLA, human leucocyte antigen MMF; mycophenolate mofetil; BK-PyVAN, BK polyoma virus-associated nephropathy
47 : What are the risk factors for BKV replication? 1. Schold JD et al Transpl Int 2009; 22: 626-34 2. Dharnidharka VR et al Transplantation 2009; 87: 1019-26 3. Hirsch HH et al N Engl J M 2009; 86-96 4. Bohl DL, Brennan DC. Clin J Am Soc Nephrol 2007; 2(Suppl 1): S36-46 5. Brennan DC et al Am J Translant 2005; 5:582-94 CsA, cyclosporine; HLA, human leucocyte antigen MMF; mycophenolate mofetil; BK-PyVAN, BK polyoma virus-associated nephropathy
48 : Immunosuppression is the main risk factor for BKV reactivation 0 100 90 80 70 60 50 40 30 20 10 Percentage (%) 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 Rejection < 12 month 1 year allograft survival Radiation Prednisone 6MP Azathioprine At Gam BKV CYA OKT3 ATG/ALG CYA ME FK506 MMF DACLIZUMAB BASILOGMAB THYMOGLOBIN SIROLIMUS FTY720 CAMPATH IH EVEROLIMUS BILATACEPT EFALIZUMAB Acott P BKV speaker meeting
49 : Tacrolimus-based regimen is a risk factor for BKV treatment 1. Schold JD et al Transpl Int 2009; 22: 626-34 a As compared to CsA modified as baseline immunosuppression BKV, BK virus; HLA human leukocyte antigen; CsA, cyclosporin Retrospective analysis of scientific registry of transplant recipients data from 34,937 kidney transplant recipients 2004-2006
50 : Pathogenesis Destruction of tubular capillary walls results in vascular spread of the virus. A heterogeneous interstitial infiltration of inflammatory cells as well as tubulitis may be absent, intermixed with the active infection, or noted in areas that lack cytopathic changes. Collateral damage with necrosis and apoptosis of noninfected tubule cells may occur. The resultant effect of continued intragraft inflammation, tubular injury, and upregulation of profibrotic mediators is allograft dysfunction and loss.
51 : Pathogenesis Once the virus has reactivated, an ascending infection via cell-to-cell spread occurs ; Without appropriate immunologic control, a progressive lytic infection ensues . This results in large nuclear and perinuclear virus-containing inclusions in the tubule cells. Lysis of these infected cells results in viral seepage into the tubule lumen and urine but also to the interstitium and propagation to surrounding cells. Subsequent tubular cell necrosis leads to cast formation and denudation of the basement membrane.
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54 : Early screening reduces risk of BK-PyVAN - BKV replication is the single common feature of all renal transplant patients at risk of BK-PyVAN 1 - guidelines recommend screening for BKV replication to identify patients at risk of BK-PyVAN - by screening, at least 80-90% of patients at risk of BK-PyVAN can be identified prior to significant histological and functional impairment 2 1. Hirsch HH et al Transplantation 2005; 79: 1277-86
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56 : Screening protocol based on plasma BKV DNA PCR. Bohl D L , Brennan D C CJASN 2007;2:S36-S46 ©2007 by American Society of Nephrology
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58 : Screening Multiple authors have recommended a step-wise approach to screening for BKV infection. Hirsch et al.  recommended initial evaluation of urine cytology (for decoy cells), viruria, or urine VP-1 mRNA load at 3-mo intervals up to 2 yr or if renal dysfunction occurs. A positive screening test is followed by quantification of DNA load in the urine (threshold >107 copies/ml), urine VP-1 mRNA (threshold >6.5 × 105 copies/ng total RNA), or plasma DNA load (threshold >104 copies/ml). If one or more of these tests is above the threshold value, then an allograft biopsy is performed. Screening for quantitative BKV DNA in plasma at 1, 3, 6, 12, and 24 mo after transplantation has been effective in detecting early infection before the occurrence of nephritis .
59 : Screening Buehrig et al. , among others, proposed use of surveillance allograft biopsies to diagnosis BKVN. Biopsies were performed at posttransplantation month 3 or 4 and at 12 mo detected 18 patients with BKVN within a 5-yr period (1996 to 2001). BKVN was diagnosed in eight patients at the time of surveillance biopsy and 10 patients during nonsurveillance. Their results showed significant improvements in graft status 6 mo after biopsy (P = 0.004) and more favorable histologic appearance at time of biopsy (P = 0.01) in the surveillance group. A trend toward earlier diagnosis of BKVN in the surveillance group was noted .
60 : Screening More recently, Khamash et al. reported superior graft survival with surveillance allograft biopsy compared with nonsurveillance in a cohort of 74 patients with a mean follow-up of 4 yr. Thus, screening for BKV infection by urine cytology, urinary or plasma BKV DNA, or renal biopsy is effective in identifying early disease.
61 : Viraemia identification of Patients at risk for BKV-PyVAN1-3 serial quantitative PCR analysis of blood can be used to follow response to treatment 2 Screening option for BKV 1. Hirsch HH et al Transplantation 2005; 79: 1277-86 2. Hirsch HH et al Am J Transplant 2009; 9(Suppl 4): S136-46 3. KDIGO Transplant Work Group Am J Transplant 2009; 9(Suppl 3): S44-58 Viruria allows early identification of patients at risk of active BKV infections 1,2 cytology is relatively inexpensive 1 Biopsy ‘Gold standard” for diagnosis of BKV replication and BK-PyVAN 1-2 Not specific for nephropathy 1,3 PCR can produce false positives 1 invasive procedure can produce false negatives; may miss focal lesions 1,2 diagnosis of acute rejection in the presence of BK-PyVAN may be difficult 1,2 Pros Cons BKV, BK virus; PCR, polymerase chain reaction BK-PyVAN, BK polyoma virus-associated nephropthy
62 : Histology The characteristic findings on light microscopy are intranuclear basophilic and gelatinous-appearing viral inclusions in epithelial cells of the urothelium . These are found in the medulla or cortex and are multifocal with random distribution. Three histologic patterns (A, B, and C) have been described ;
63 : Histology In early disease (pattern A), the cytopathic changes are present with little to no inflammation or tubular atrophy. Pattern B consists of viral cytopathic changes with varying degrees of inflammation, tubular atrophy, and fibrosis. In late BKV nephropathy (pattern C), cytopathic changes often are less apparent as a result of a background of tubular atrophy, interstitial fibrosis, and chronic inflammatory infiltrate. The degree of damage corresponds to the degree of allograft dysfunction and allograft outcome
64 : Histology The distinction of BKV nephropathy from acute tubular necrosis, interstitial nephritis, and acute cellular rejection is difficult and aided by assessment of blood or urine PCR. Absence of definitive features of acute cellular rejection such as endotheliitis and absence of C4d deposits in peritubular capillaries are helpful. Other histopathologic changes include glomerular crescents (10 to 20%) , ischemic glomerulopathy (62%) , transplant glomerulopathy (62%) , abundant plasma cell infiltrates (up to 75%), and tubular microcalcifications (25%) . Features of calcineurin inhibitor toxicity such as striped fibrosis , thrombotic microangiopathy , and tubular isometric vacuolization may also be present.
65 : Urine shedding of BKV is more prevalent than viremia. BKV infected renal tubular epithelial (decoy-enlarged nucleus with a single large basophilic intranuclear inclusion) cells appear to deteriorate quickly (within minutes), which may limit urine microscopy as a screening tool -not sensitive or specific. Decoy cells BK virus Diagnosis & monitoring PCR Viral DNA in the plasma (> 10,000 copies/ml) or urine (10,000,000copies/ ml) 100% sensitivity, 88% specificity
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68 : pathology BKV nuclear incusions Type I: An amorphous ground-glass variant “ Ground-glass” appearance of nucleus Type II: granular variant surrounded by a “halo” Type III: a finely granular variant without halo Type II/III hybrid: Intranuclear vesicles Type IV: a vesicular variant with clumped, irregular chromatin BK virus Diagnosis & monitoring Allograft biopsy Characteristic intranuclear viral inclusions Positive immunohistochemical staining/ in-situ hybridization of the infected cells Viral particles by EM
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70 : BKV nephropathy. Bohl D L , Brennan D C CJASN 2007;2:S36-S46 ©2007 by American Society of Nephrology
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72 : Screening for BKVN and therapeutic intervention Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008
73 : Type and prevalence of BK virus (BKV) infections in kidney transplant recipients. Bohl D L , Brennan D C CJASN 2007;2:S36-S46 ©2007 by American Society of Nephrology
74 : Possible interventions following BK viraemia and / or BK-PyVAN Immunosuppression reduction Switching immunosuppressive regimen Adjunctive therapies Hirsch HH et al Am J Transplant 2009; 9(Suppl 4): S136-46 KDIGO Transplant Work Group
75 : Early reduction in immunosuppression is associated with resolution of BKV replication and BK-PyVAN prevention BKV, BK virus; BK-PyVAN, BK polyoma virus-associated nephropthy
76 : Reducing immunosuppression in line with KDIGO and AST guidelines B, moderate evidence to support a recommendation for use; B-III, evidence from opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committee KDIGO, kidney disease, improving global outcomes; AST, American Society of Transplant Surgeons; MMF, mycophenolate mofetil; CsA cyclosporin
77 : BKV / polyoma-related AEs with reduced CsA + mTORi vs CsA + MPA A2309: multicentre, randomised trial of 833 de novo renal transplant patients randomised to everolimus + reduced CsA or MPA + standard CsA with basiliximab ± steroids 10 8 6 4 2 0 Everolimus 1.5 mg + low CsA Incidence at 12 months (%) collected by AE reporting 2.5 Polyoma virus and/or BKV Everolimus 3.0 mg + low CsA 1.1 EC-MPS+ standard CsA 5.1 Lowest incidence of BKV / polyoma viral infection seen with low CsA and everolimus BPAR, % 16.2 13.3 17.0 CsA through levels (CO), 100-200 ng/mL starting from day 5; 75-150 ng/mL starting from Month 2, 50-100 ng/mL starting from month 4; 25-50 ng/mL starting from month 6 CsA, cyclosporine; ME, microemulsion, MMF; mycophenolate mofetil; BK-PyVAN, BK virus, AE, adverse event Tedesco-Silva Jr H et al Am J Transplant 2010; 10: 1401-13
78 : DIRECT study: lower incidence of BKV replication with CsA vs tacrolimus Hirsch HH et al Am J Transplant 2009; 9(suppl2): 337; abs 505 25 20 15 10 5 0 Tacrolimus (n=247) 25 20 15 10 5 0 BK, BK virus; CsA, cyclosporine, MPA, mycophenolic acid CsA (n-215) 23 17 p=0.0739 BK viruria cGFR (mL/min) 12 5 p=0.0053 BK viraemia DIRECT: randomised, open-label study of 682 de novo renal transplant patients randomised to CsA or tacrolimus with MPA, steroids and basiliximab induction Tacrolimus (n=256) CsA (n-231)
79 : Treatment of “definitive” BKVN Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008 The therapeutic mainstay is reduction of maintenance immunosuppression Antivirals and other pharmacologic approaches have been variably associated
80 : Early diagnosis has allowed a significant amelioration of prognosis graft outcome: no screening: 35-50% of BKVN treated with any protocol ? marked graft dysfunction, with possible progression to graft loss; screening and early treatment: no graft loss, milder graft dysfunction. Treatment of “definitive” BKVN: results Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008
81 : Preemptive treatment of BKVN On the basis of plasma BKV-DNA analysis DNA threshold for treatment: >104 ge/ml graft outcome: viremia clearance, no BKVN, no acute rejection Ginevri F, Hirsch HH. BK polyomavirus nephropathy. 2008
82 : Postinfection Monitoring Failure to clear BKV leads to worse graft function and outcomes. Because histologic clearance of the virus and disappearance of decoy cells precede clearance from the blood, monitoring should be performed with quantitative assays, preferably BKV PCR, until the viral level is undetectable or at least falls below the threshold value that is associated with BKV nephropathy. On the basis of kinetic models and prospective monitoring , viremia clears in 7 to 20 wk, but the initial decrease may be delayed by 4 to 10 wk after immunosuppression reduction
83 : Postinfection Monitoring If viremia persists, then further reduction of current maintenance therapy, conversion to sirolimus, or addition of leflunomide can be considered. Twelve weeks after the initial immunosuppression reduction, Wali et al.  described three recipients who had persistent viremia and responded to further reduction in immunosuppression by conversion to sirolimus (target level 10 to 12 ng/ml) and low-dosage prednisone (2.5 mg every other day).
84 : BKV Nephropathy and Acute Rejection The treatment of recipients whose biopsy shows rejection with concurrent BKV nephropathy or early after reduction of immunosuppression to treat BKV nephropathy remains problematic. More than half of biopsies may show tubulitis and reduction in immunosuppression can precipitate rejection in 10 to 30% of recipients.
85 : BKV Nephropathy and Acute Rejection The infiltrating mononuclear cells may represent a BKV-specific and/or allospecific response, and treatment is debatable . Studies that compared BKV nephropathy with acute rejection have identified differences in the proportion and type of infiltrating cell , protein expression and proteomic profiles , and gene expression profiles . However, these differences have not been characterized serially after modification in immunosuppression.
86 : BKV Nephropathy and Acute Rejection However, the presence of atypical features such as strong peritubular capillary C4d staining, vasculitis, glomerulitis, or interstitial hemorrhage would support rejection and require an individualized approach. The delayed improvement in creatinine after reduction in immunosuppression likely reflects the slow resolution of the cellular infiltrate. On follow-up biopsy, a cellular infiltrate with or without tubulitis in the setting of persistent BKV viremia is consistent with resolving BKV nephropathy and continued monitoring. 
87 : BKV Nephropathy and Acute Rejection Once BKV nephropathy and viremia have cleared, the benefit of uptitrating immunosuppression to prevent chronic rejection or late acute rejection remains unknown.
88 : Are BKV-specific T cells protective or destructive? BKV specific T cell immunity Acute BKV reactivation chronic BKV infection Low-level inflammation Massive inflammation T cell control BKV reactivation Cytotoxic T cells damage the graft Reduction of immunosuppression Is required Reduction of immunosuppression Is harmful
89 : I/R preinjury allorectivity (marginal organs) Latently inspected kidney BKV reactivation immunosppression Sufficient T cell control No problem amplification Slow onset of T-cell response insufficient functionally protracted virus control persistent inflammation
90 : I/R preinjury allorectivity (marginal organs) Latently inspected kidney BKV reactivation immunosppression amplification Slow onset of T-cell response insufficient functionally protracted virus control persistent inflammation Decreasing Immunosuppression 60-80% response
91 : I/R preinjury allorectivity (marginal organs) Latently inspected kidney BKV reactivation immunosppression amplification Slow onset of T-cell response insufficient functionally protracted virus control persistent inflammation Decreasing Immunosuppression 60-80% response
92 : I/R preinjury allorectivity (marginal organs) Latently inspected kidney BKV reactivation immunosppression amplification Slow onset of T-cell response insufficient functionally protracted virus control persistent inflammation Inhibiting inflammation By IVIG or leflunomide: In some case reports
93 : I/R preinjury allorectivity (marginal organs) Latently inspected kidney BKV reactivation immunosppression amplification Slow onset of T-cell response insufficient functionally protracted virus control persistent inflammation Inhibiting APC ???
94 : Targeting antigen presentation Dendritic cells Primed B cells Primed B cells Monocytes/macrophages The most effective APC of memory / effector T cells Naive Central memory Effector / memory
95 : Targeting B lymphocytes B cells Targeting CD20 by rituximab useful in BKV nephropathy? Stasi R et. Al 2006
96 : Rescue treatment of therapy - resistant BKVAN by rituximab Minimizing IS (FK ->CsA, MMF ->AZA, MP) + Cidofovir 0.25 mg/kg/week I.V. Rituximab 375 mg/m2 weekly for 3 weeks follow-up > 2yr BKV nephropathy Non-responders (50%) Responders (>80%)
97 : Retransplan tation Retransplantation in patients with graft loss caused by polyoma virus nephropathy Ramos, Emilio1 8; Vincenti, Flavio3; Lu, Wei X.1; Shapiro, Ron4; Trofe, Jennifer5; Stratta, Robert J.6; Jonsson, Johann7; Randhawa, Parmjeet S.4; Drachenberg, Cinthia B.2; Papadimitriou, John C.2; Weir, Matthew R.1; Wali, Ravinder K.1
98 : Retransplantation The characteristics and outcome in 10 patients who underwent retransplantation after losing their renal grafts to BK virus-associated nephropathy (BKAN) are described. The patients underwent retransplantation at a mean of 13.3 months after failure of the first graft. Nephroureterectomy of the first graft was performed in seven patients. Maintenance immunosuppression regimens after the first and second grafts were similar, consisting of a combination of a calcineurin inhibitor, mycophenolate mofetil, and prednisone. BKAN recurred in one patient 8 months after retransplantation, but stabilization of graft function was achieved with a decrease in immunosuppression and treatment with low-dose cidofovir. After a mean follow-up of 34.6 months, all patients were found to have good graft function with a mean creatinine of 1.5 mg/dL
99 : Newer trends Urinary biomarkers Urinary HLA-DR and CD54 expression--indicators for inflammatory activity in decoy cell shedding patients. Kim SH, Ahn HJ, Kim YS, Kim SI, Kim HS, Jeong HJ. Quantitation of viral DNA in renal allograft tissue from patients with BK virus nephropathy. Randhawa PS, Vats A, Zygmunt D, Swalsky P, Scantlebury V, Shapiro R, Finkelstein S
100 : BKVN is an important problem after renal transplantation that has limited improvements in graft survival. Increasing awareness of this condition, utility of BKV DNA estimation in blood and urine, careful renal histological evaluation, and avoiding further aggressive immunosuppression after the diagnosis of BKVN are changing the outcome of this disease. Screening for BKV in blood and urine, along with pre-emptive reduction in immunosuppression, has been a useful strategy to prevent BKVN. The role of BKV-specific antibody and host cellular immunity in the pathogenesis of BKVN is evolving.
101 : KDIGO RECOMMENDATIONS-Routine Screening after Kidney Transplantation
102 : KDIGO RECOMMENDATIONS-Vaccination 12.1: We recommend giving all KTRs approved, inactivated vaccines, according to recommended schedules for the general population, except for HBV vaccination. (1D) 12.1.1: We suggest HBV vaccination (ideally prior to transplantation) and HBsAb titers 6–12 weeks after completing the vaccination series. (2D) 12.1.1.1: We suggest annual HBsAb titers. (2D) 12.1.1.2: We suggest revaccination if the antibody titer falls below 10mIU/mL. (2D)
103 : KDIGO RECOMMENDATIONS-Vaccination 12.2: We suggest avoiding live vaccines in KTRs. (2C) 12.3: We suggest avoiding vaccinations, except influenza vaccination, in the first 6 months following kidney transplantation. (2C) 12.3.1: We suggest resuming immunizations once patients are receiving minimal maintenance doses of immunosuppressive medications. (2C) 12.3.2: We recommend giving all KTRs, who are at least 1-month post-transplant, influenza vaccination prior to the onset of the annual influenza season, regardless of status of immunosuppression. (1C)
104 : KDIGO RECOMMENDATIONS-Vaccination 12.4: We suggest giving the following vaccines to KTRs who, due to age, direct exposure, residence or travel to endemic areas, or other epidemiological risk factors are at increased risk for the specific diseases: • rabies, (2D) • tick-borne meningoencephalitis, (2D) • Japanese B encephalitis—inactivated, (2D) • Meningococcus, (2D) • Pneumococcus, (2D) • Salmonella typhi—inactivated. (2D)
105 : KDIGO RECOMMENDATIONS-Vaccination 12.4.1: Consult an infectious disease specialist, a travel clinic or public health official for guidance on whether specific cases warrant these vaccinations. (Not Graded)
106 : Recommended Vaccines after Kidney Transplantation-KDIGO Diphtheria—pertussis–tetanus Haemophilus influenza B Hepatitis A Hepatitis B Pneumovax Inactivated polio Influenza types A and B (administer annually) Meningococcus: administer if recipient is in high risk Typhoid Vi Consider providing booster polysaccharide pneumococcal vaccination every 3–5 years.
107 : Contraindicated Vaccinations after Transplantation-KDIGO Varicella zoster BCG Smallpox Intranasal influenza Live oral typhoid Ty21a and other newer vaccines Measles (except during an outbreak) Mumps Rubella Oral polio Live Japanese B encephalitis vaccine Yellow fever
108 : KDIGO RECOMMENDATIONS Viral Diseases 13.1: BK POLYOMA VIRUS 13.1.1: We suggest screening all KTRs for BKV with quantitative plasma NAT (2C) at least: • monthly for the first 3–6 months after transplantation (2D); • then every 3 months until the end of the first post-transplant year (2D); • whenever there is an unexplained rise in serum creatinine (2D); and • after treatment for acute rejection. (2D)
109 : KDIGO RECOMMENDATIONS Viral Diseases 13.1.2: We suggest reducing immunosuppressive medications when BKV plasma NAT is persistently greater than 10,000 copies/mL (107 copies/L). (2D)
110 : KDIGO RECOMMENDATIONS Viral Diseases 13.3: EPSTEIN-BARR VIRUS AND POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE 13.3.1: We suggest monitoring high-risk (donor EBV seropositive/recipient seronegative) KTRs for EBV by NAT (2C): • once in the first week after transplantation (2D); • then at least monthly for the first 3–6 months after transplantation (2D); • then every 3 months until the end of the first post-transplant year (2D); and • additionally after treatment for acute rejection. (2D)
111 : KDIGO RECOMMENDATIONS Viral Diseases 13.3.2: We suggest that EBV-seronegative patients with an increasing EBV load have immunosuppressive medication reduced. (2D) 13.3.3: We recommend that patients with EBV disease, including PTLD, have a reduction or cessation of immunosuppressive medication. (1C)
112 : KDIGO RECOMMENDATIONS Viral Diseases 13.4: HERPES SIMPLEX VIRUS 1, 2 AND VARICELLA ZOSTER VIRUS 13.4.1: We recommend that KTRs who develop a superficial HSV 1, 2 infection be treated (1B) with an appropriate oral antiviral agent (e.g. acyclovir, valacyclovir, or famciclovir) until all lesions have resolved. (1D) 13.4.2: We recommend that KTRs with systemic HSV 1, 2 infection be treated (1B) with intravenous acyclovir and a reduction in immunosuppressive medication. (1D)
113 : KDIGO RECOMMENDATIONS Viral Diseases 13.4.2.1: We recommend that intravenous acyclovir continue until the patient has a clinical response, (1B) then switch to an appropriate oral antiviral agent (e.g. acyclovir, valacyclovir, or famciclovir) to complete a total treatment duration of 14–21 days. (2D) 13.4.3: We suggest using a prophylactic antiviral agent for KTRs experiencing frequent recurrences of HSV 1,2 infection. (2D) 13.4.4: We recommend that primary VZV infection (chicken pox) in KTRs be treated (1C) with either intravenous or oral acyclovir or valacyclovir; and a temporary reduction in amount of immunosuppressive medication. (2D)
114 : KDIGO RECOMMENDATIONS Viral Diseases 13.4.4.1: We recommend that treatment be continued at least until all lesions have scabbed. (1D) 13.4.5: We recommend that uncomplicated herpes zoster (shingles) be treated (1B) with oral acyclovir or valacyclovir (1B), at least until all lesions have scabbed. (1D) 13.4.6: We recommend that disseminated or invasive herpes zoster be treated (1B) with intravenous acyclovir and a temporary reduction in the amount of immunosuppressive medication (1C), at least until all lesions have scabbed. (1D)

 

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an important oppurtunistic infection especially in post transplant setting
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