BKV INFECTION.......................pptx

BKV INFECTION

1. BKV INFECTION

2. Polyomaviruses Double-stranded DNA (dsDNA) viruses. BK virus and JC virus BK virus resides in latency in renal tubular epithelial cells. JC virus also has been isolated from renal tissues but tropism for neural tissues Hogan et al. and Gardner et al. found that the pre transplantation seroprevalence was 80 to 88% for BKV and 54 to 55% for JCV

3. BKV First isolated from an immunosuppressed renal transplant recipient with ureteric stenosis in 1971 The term “BK” originated from that patient’s initials. BKV causes a common childhood infection without major clinical sequelae, and 80% of adults are seropositive for BKV After primary infection, BKV remains dormant and does not cause significant morbidity in healthy individuals

4. Clinically significant reactivation of latent BKV occurs in some immunosuppressed individuals, such as following HIV infection or transplantation BK virus is associated with a range of clinical syndromes in immunocompromised hosts, including viruria and viremia, ureteral ulceration and stenosis, and hemorrhagic cystitis. 19.5% of KTRs experience BK viremia post transplantation. Active infection of renal allografts has been associated with progressive loss of graft function (“BK nephropathy”) in approximately 4% (range 1–8%) of kidney transplant recipients; this is referred to as PVAN

5. Epidemiology Three polyomaviruses—JCV, BKV, and SV40—cause disease in humans. Humans are the natural host for JCV and BKV BKV is acquired during childhood, and seroprevalence stabilizes or wanes with increasing age . In contrast, JCV seroprevalence increases with age. The primary infection may be fecal-oral, respiratory, transplacental , or from donor tissue During a viremic phase, the virus infects target tissues, including the uroepithelium , lymphoid tissue, and brain , establishing a latent or permissively lytic infection.

6. SV40, a simian virus, was introduced into the human population through contaminated polio and adenovirus vaccines It can be acquired through close contact with nonhuman primates and may spread at a low rate from person to person Although SV40 has been identified in kidney transplant biopsies and associated with native kidney diseases , its importance in kidney transplantation is poorly defined

7. Virology Small, nonenveloped viruses with an icosahedral capsid and a core of circular double-stranded DNA in association with histones The genome is transcribed bidirectionally . It encodes for The early regulatory proteins—small t antigen and large T antigen The late structural proteins—VP1, VP2, and VP3.

8. The capsid consists of 72 pentamers , each with five VP1 proteins and a central VP2 or VP3 protein. VP1 binds the sialic acid residues of its receptor onto permissive cells The gangliosides GD1b and GT1b and (Alpha 1,2)linked sialic acids on N-linked glycoproteins can act as the receptor for BKV After attachment, BKV is internalized via caveolae -mediated endocytosis Once inside the cell, the viruses traffic to the nucleus and establish a latent or lytic infection

9. Pathogenesis Replication of BKV occurs during states of immune suppression. BKV viruria occurs in pregnancy, cancer, HIV infection,diabetes , and transplantation BKV viremia and BKV nephropathy, however, are rare outside of kidney transplantation. BKV viremia occurs in 13% and BKV nephropathy in 8% of kidney transplant recipients

10. In a kidney transplant recipient, BKV reactivation can come from the donor or the recipient. Recipients who had BKV infection and received a kidney from the same donor have been shown to have identical BKV genotypes, supporting donor transmission Recipients whose donors had higher BKV antibody titers were more likely to develop BKV infection than those with lower titers, also supporting donor transmission Injury is also believed to contribute to reactivation

11. In a mouse polyomavirus model, mechanical or chemical injury allowed for initiation of acute infection and also reactivation of latent polyomavirus In humans, injury could come from ischemia or stent placement,or rejection could allow for new infection and reactivation of latent infection in either the donor or recipient.

12. 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.

13. 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 Destruction of tubular capillary walls results in vascular spread of the virus

14. A heterogeneous interstitial infiltration of inflammatory cells as well as tubulitis , 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.

15. Early retrospective studies identified tacrolimus and mycophenolate mofetil (MMF) as risk factors for BKV nephropathy More recent retrospective studies found BKV nephropathy associated with the combination of tacrolimus levels (8 ng/ml) and MMF dosages (1.5 to 2 g/d) BKV nephropathy has been reported with triple drug regimens that include a calcineurin inhibitor , an adjuvant agent (MMF, azathioprine, or sirolimus ) and prednisone, calcineurin -free triple drug therapy, double therapy with a calcineurin inhibitor and sirolimus , tacrolimus monotherapy and with or without use of an induction agent It is the net state of immunosuppression and not a specific drug that allows for development of progressive BKV infection

16. Immunology Although polyomavirus reactivation is common, clinically significant disease is unusual. This is because most recipients are able to control the viruses. Persistent viral infections, such as polyomaviruses, cannot be completely cleared and require continuous immune control BKV replication typically begins early after transplantation and after treatment of rejection when immunosuppression is greater and immune control is reduced.

17. Although 60 to 80% of recipients are BKV seropositive before transplantation , the presence of these BKV-specific antibodies has not been shown to prevent development of BKV infection BKV-specific antibodies can inhibit BKV infectivity A graded protective effect of the titer of recipient BKV-specific antibodies before transplantation has been suggested BKV seronegativity is also a risk factor for BKV viruria and nephropathy in children

18. In adults, Shah et al reported that seropositive donors and seronegative recipients (BKV D+/R-) developed a serologically defined BKV infection most frequently 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

19. Reduction in immunosuppression results in a significant increase in BKV-specific IgG antibody titers , emergence of BKV-specific cellular immunity , clearance of viremia, and stabilization of graft function . The presence of BKV antibodies seems to have a limited role Comoli et al. found that despite persistently elevated BKV antibody titers, recurrent BKV viremia was associated with a low frequency of IFN-– producing cells.

20. Prosser et al . used an IFN-enzyme-linked immunosorbent spot (ELISPOT) assay to measure cellular immune response directed against BKV large T antigen in patients with BKVN at the time of diagnosis and after full resolution of infection. A robust 400% increase in IFN- activity was noted with resolution of BKVN

21. 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.

22. Within the viral genome, both the large T antigen and VP1 gene products have been shown to contain epitopes that are responsible for CD4 and CD8 cell recognition Stronger T cell response was associated with lower viral load, whereas a weaker response was associated with higher viral load and viral persistence. Thus, regions in both the VP1 and large T antigen gene products contain conserved sequences that likely are responsible for cellular immunity against BKV

23. 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.

24. Occurrence of BKVN in renal transplant recipients as opposed to liver and heart transplant recipients unveils a potential role of alloimmune activation in renal grafts with BKV activation and frank nephritis The occurrence of BKVN correlates with a higher degree of HLA mismatches possibly mediated by More episodes of rejection, intense immunosuppression, and impaired cytotoxicity in an allogeneic environment but less allograft loss

25. Investigators from Emory University showed using a mouse polyoma transplant model that polyoma viral nephritis occurs only in the presence of alloimmune activation. Thus, subclinical alloimmune activation in renal grafts may trigger BKV replication and nephritis and explains why this is specific to renal grafts.

26. Drachenburg et al. showed an inverse relationship between the level of HLA matches and graft survival in patients with BKVN. Patients who maintained graft function had lower mean HLA match of 1.5 as opposed to 2.87 among those who lost their graft Lack of HLA matches as a predictor of better outcome in patients with BKVN. The antiviral immune response is likely to trigger a variety of nonspecific inflammatory and fibrogenic mechanisms that lead to graft failure Lack of HLA donor–recipient matching may result in the inability of the host to mount an efficient specific antiviral immune response. Thus, lack of HLA matches may be beneficial in patients with BKVN.

27. Clinical Features In kidney transplant recipients, BK polyomavirus replication typically develops in stages: viruria followed by viremia and then, if viral replication persists, nephropathy  Occurs within the first year after transplantation . Patients with BKVN usually remain asymptomatic and are detected when they experience renal insufficiency Renal dysfunction secondary to ureteric stricture leading to hydronephrosis is occasionally seen Severe systemic disease leading to multiorgan failure has been reported

28. Viruria and viremia Earliest manifestation of BKV infection in kidney transplant recipients, affecting approximately one-quarter to one-third of patients during the first year following transplantation . Most, viruria is asymptomatic, detected only by screening, and does not progress to viremia  Viruria is a sensitive marker for progression to BKV-associated nephropathy , it is nonspecific

29. Urine decoy cells (renal tubular or uroepithelial cells containing intranuclear viral inclusions), which typically represent higher-level viruria , may be present at this stage Papanicolaou stain 100% sensitivity for BK virus infection but a low (29%) predictive value

30. Types 1-4  Most common are classic decoy cells characterized by large, homogenous, amorphous ground-glass like intranuclear inclusion bodies and a condensed rim of chromatin (type 1) 

31.  Decoy cells reveal granular intranuclear inclusions surrounded by a clear halo, i.e., cytomegalovirus (CMV)-like (type 2)

32. Multinucleated decoy cells with granular chromatin are detected (type 3)

33. Type 4 decoy cells with vesicular nuclei and a distinct network of coarsely granular and clumped chromatin

34. Viremia may follow viruria in a few weeks and occurs most frequently in those with high urine viral loads and sustained viruria Viremia is detected in 10 to 30 percent of recipients in the first six months posttransplantation and in 5 to 10 percent of recipients thereafter. Viremia is typically asymptomatic. Viremia has a greater predictive value than viruria for progression to BKVAN

35. Viremia is present in nearly all patients with BKVAN and has a positive predictive value of approximately 40 to 65 percent for the development of BKVAN Because BKVAN can quickly follow viremia ( eg , within one to two weeks) and damage to the graft can be irreversible, viremia is a generally accepted indication to reduce immunosuppression in kidney transplant recipients. As with viruria , higher viral loads and sustained viremia have greater predictive value for concomitant or progression to biopsy-confirmed BKVAN

36. BKV-associated nephropathy (BKVAN) Asymptomatic viruria , viremia, and/or a slow progressive rise in serum creatinine are typically the only indicators of BKVAN. The incidence of BKVAN is highest in the first two to six months posttransplant . The incidence of late BKVAN appears to be highest in patients with multi-organ transplants and is related to the more intensive immunosuppressive regimens used for these patients.

37. Without resolution of infection, progressive renal allograft dysfunction and graft loss can ensue over a period of months . Within the allograft, early infection triggers interstitial inflammation, which then progresses to fibrosis and tubular injury. Accordingly, urinalysis may reveal pyuria, hematuria, and/or cellular casts consisting of renal tubular cells and inflammatory cells, or may be normal.

38.  Historically, BKVAN was associated with graft loss rates that exceeded 50 percent However, with the implementation of standardized screening protocols, rates of short-term graft loss have fallen substantially

39. Other manifestations   Hemorrhagic cystitis is a rare manifestation of BKV infection in kidney transplant recipients The most commonly reported manifestation of BKV infection among hematopoietic cell transplant recipients  Putative link between BKV and the development of genitourinary cancers in animal models Role for BKV and human malignancies has not been definitively established

40. Diagnosis The presence of decoy cells is a good screening test but not diagnostic of BKVN Three-dimensional cast-like polyomavirus aggregates , minimum of six ,termed “ Haufen ” (after the German word for “cluster or stack”) by electron microscopy (EM) in urine

41. The qualitative detection of Haufen was 100% sensitive and 99% specific for identifying biopsy-proven BKN. It closely reflected the clinical disease course with PPV and NPV of 97 and 100%, respectively. Harsharan K. Singh et al J Am Soc Nephrol 20: 416–427 , 2009.

42. Plasma quantitative PCR The detection of BKV viremia by plasma quantitative PCR to VP1 is both highly sensitive (100 percent) and specific (88 percent) for the diagnosis of BKVAN Has a higher positive predictive value for BKVAN than the detection of viruria by urine quantitative PCR or urine cytology (50 to 60 percent VS  40 and 29 percent)  Can be used to monitor the patient's response to therapy since a decrease in BKV viremia usually occurs soon after a reduction in immunosuppression and precedes a decrease in viruria by weeks to months

43.  BKV viral load of ≥10,000 (10 4)copies/mL, ( > 4 log copies/ml)particularly when sustained for more than three weeks' duration, is highly suggestive of BKVAN (" presumptive" BKVN) Urine quantitative PCR    High sensitivity and less invasive ( Possible BKVN) Needs confirmation with plasma PCR since one-half of patients with BKV viruria will not develop viremia or BKVAN.   Not as useful as plasma PCR for monitoring the response to therapy, since changes in the urine viral load lag behind changes in the plasma viral load upon lowering immunosuppression. 

44. RENAL BIOPSY Gold standard At least two cores including medulla should be examined. TIN , intranuclear inclusion bodies IHC for SV 40 Large T antigen

45. A definitive diagnosis of BKVN requires the following findings on kidney biopsy Characteristic cytopathic changes. plus Positive immunohistochemistry tests using antibodies directed specifically against BKV or against the cross-reacting SV40 large T antigen. Positive SV40 staining is associated with a specificity of almost 100 percent for polyomavirus nephropathy (PVN) Does not distinguish between BKV- and JC virus (JCV)-associated cases.

46. Histologic findings Intranuclear basophilic viral inclusions without a surrounding halo CMV has cytoplasmic inclusions, as noted above, and HSV has both intranuclear and cytoplasmic inclusions Anisonucleosis , hyperchromasia , and chromatin clumping of infected cells Interstitial mononuclear or polymorphonuclear cell infiltrates in the areas of tubular damage . Tubular injury, which is characterized by tubular cell apoptosis, cell drop out, desquamation, and flattened epithelial lining 

47. Tubulitis , which is manifested by lymphocyte permeation of the tubular basement membrane.  With electron microscopy, intranuclear viral inclusions (with a diameter size of 30 to 50 nm) and tubular damage characterized by tubular cell necrosis, prominent lysosomal inclusions, and luminal protein and cellular casts  Three histologic patterns (A, B, and C) have been described

48.  Three histologic classes of definitive (biopsy-proven) PVN on the basis of two morphologic variables: intrarenal polyomavirus replication/load levels ( pvl ) and Banff interstitial fibrosis (ci) scores The pvl score is based upon the extent of virally induced tubular changes. A tubule with intranuclear viral inclusion bodies (type 1 or 2) and/or a positive immunohistochemical reaction for SV40 large T antigen in one or more cells per tubular cross-section is considered "a positive tubule."

49. The overall percentage of positive tubular cross-sections is estimated in the entire biopsy sample ( ie , all available cores and all tubules/ducts in the cortex and medulla) Three levels of pvl are defined: pvl 1 = <1 percent, pvl 2 = 1 to 10 percent, pvl 3 = >10 percent positive tubules/ducts.

50.  The three histologic classes of PVN are as follows: PVN class 1 – pvl 1, ci ≤1 PVN class 2 – pvl 1, ci ≥2  or  pvl 2, any ci score  or  pvl 3, ci ≤1 PVN class 3 – pvl 3, ci ≥2  Interstitial inflammation and tubulitis can vary from Banff scores ti 0 to ti 3/t0 to t3

51. PVN 1

52. PVL 3

53. In a retrospective analysis of 178 patients with biopsy-proven BKVN, the Banff classification system was shown to correlate with clinical outcomes 25, 63, and 12 percent of patients were categorized as PVN class 1, 2, and 3, respectively. At 24 months after the initial diagnostic renal allograft biopsy, the median increase in serum creatinine was 0.4 mg/ dL , 1.0 mg/ dL , and 4.8 mg/ dL for patients with PVN class 1, 2, and 3, respectively. Graft failure occurred in 16, 31, and 50 percent of patients with PVN class 1, 2, and 3, respectively.

54. Distinguishing BKVN from rejection  Presence of BKV inclusions and immunohistologic or in situ hybridization evidence of virally infected tubular epithelial cells  Correlate the histologic findings with PCR evidence of viremia   The presence of extensive tubulitis in areas remote from the viral cytopathic changes suggests that acute rejection is present, in addition to BKVN. The combined presence of endarteritis, fibrinoid vascular necrosis, glomerulitis , and C4d deposits along peritubular capillaries is conclusive evidence of concurrent rejection Some patients with BKVN without concurrent rejection may have C4d deposits in the tubular basement membrane

55. Immunohistochemical staining of renal tissue or urinary sediment with anti–HLA-DR associated with acute rejection A higher proportion of CD20+ cells in the infiltrates in the kidney has been correlated with BKVN as opposed to acute rejection

56. SCREENING  ( kdigo ) 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) 13.1.2 : We suggest reducing immunosuppressive medications when BKV plasma NAT is persistently greater than 10 000 copies/mL (10 7 copies/L). (2D)

57. The use of urine screening requires performance of NAT on the blood of those patients whose level of BK viruria exceeds established thresholds. Accordingly, it is suggested that NAT be performed on plasma, and not the urine of KTRs. When NAT is not available, microscopic evaluation of the urine for the presence of decoy cells is an acceptable, alternative screening method for BKV disease and the risk for BKV nephropathy

58. A threshold plasma BKV level of > 10 000 copies/mL (107 copies/L) is associated with a 93% specificity for the presence of BKV nephropathy. In those with levels above thrshhold reduction of immunosuppression can result in a decrease in BKV load and a concomitant reduction of risk of development of BKV nephropathy . Monitor the viral load every two to four weeks thereafter to ensure that it is downtrending A RCT reported that withdrawal of the antimetabolite resulted in clearance of viremia without progression to BKV nephropathy

59. The international consensus group recommended performance of kidney biopsy for asymptomatic patients with an elevated BKV load When a kidney biopsy is obtained, it should be evaluated for the presence of BKV using the cross-reacting antibody for simian virus 40. However, other experts have not recommended the performance of a kidney biopsy for these patients

60. Treatment The principal treatment for BKV nephropathy is reduction in immunosuppression BKV nephropathy seems to develop less frequently with maintenance protocols that involve steroid withdrawal . When BKV nephropathy is diagnosed early within the first 6 mo after transplantation and the creatinine is stable, survival is improved compared with when the diagnosis is made later and the creatinine is elevated

61. Early or Presumptive BKV Nephropathy

62. Brennan et al. showed that preemptive withdrawal of the antimetabolite upon detection of viremia prevented BKV nephropathy without significantly increasing the risk for rejection Viremia cleared in 22 (96%) of 23 recipients with only one episode of acute rejection directly related to immunosuppression reduction. 27% required withdrawal of the antimetabolite followed by reduction in calcineurin inhibitor for persistent viremia.

63. In paediatric Tx , Hymes and Warshaw cleared viremia in 58% of recipients with presumptive nephropathy after a 50% reduction in the dosage of mycophenolate or sirolimus and targeting tacrolimus troughs of 3 to 5 ug /dl. Approaches to reducing immunosuppression vary among transplant centers, and there are no randomized controlled trials comparing different protocols.  Monitor the plasma quantitative PCR every one to two weeks until BKV DNA is undetectable for two consecutive tests obtained at least one week apart

64. Monitor the serum creatinine level weekly. If the serum creatinine level increases by ≥25 percent from baseline at any time while immunosuppression is being reduced, the patient should be evaluated for the possibility of acute rejection

65. PRE emptive rx Reduce the dose of the antimetabolite by 50 percent. If the BKV viral load does not decrease within two to four weeks, completely discontinue the antimetabolite. If there is still no decrease in viral load after another two weeks, decrease the dose of the calcineurin inhibitor by 25 to 50 percent, targeting a whole blood tacrolimus trough level of 4 to 6 ng/mL or a whole blood cyclosporine trough level of 60 to 100 ng/ mL.

66. Conversion from tacrolimus to cyclosporine may lower MMF levels if dosages of MMF remain the same It is interesting that cyclosporine in vitro but not tacrolimus in vitro has been shown to inhibit BKV reactivation

67. Treating biopsy-proven BKV nephropathy The treatment of BKV nephropathy is unsatisfactory. Some centers that would use antiviral therapy (including cidofovir , leflunomide and/or ciprofloxacin) as treatment To date there are no definitive data confirming their effectiveness. Reduction of immunosuppression does appear to have some impact on BKV nephropathy

68. KDIGO GUIDELINES A common practice of immunosuppressive dose reduction is withdrawal of antimetabolite (azathioprine or MMF) and reduction in CNI dosage by 50%. Switching from the antimetabolite MMF or EC-MPS to leflunomide (an immunosuppressive agent with antiviral activity) has been associated with declining BKV load in blood and improving histology

69. Adjunctive therapies Intravenous IG   Commercially available IVIG preparations contain BKV-neutralizing antibodies against all major genotypes  Use of IVIG may be considered in patients with established BKVN who Do not respond to a reduction in immunosuppression Also have severe hypogammaglobulinemia ( ie , immunoglobulin G [IgG] <400 mg/ dL ) Dose of 300 mg/kg every three weeks in conjunction with a reduction in immunosuppression  Goal of maintaining an IgG level >400 mg/ dL

70. Leflunomide Prodrug whose antimetabolite, A77 1726, has both immunosuppressive and antiviral activity  Hematologic toxicity and hepatotoxicity

71. Leflunomide treatment is limited because of the requirement of large doses of drug, necessity for liver function monitoring to detect liver toxicity, and need for therapeutic monitoring of trough A77 1726 levels for effectively treating this infection  In a phase II randomized trial, an investigational agent derived from an active metabolite of  leflunamide (FK778) provided no clinically significant benefit compared with the reduction of immunosuppressive agents 

72.   Cidofovir Nucleotide analog of cytosine that is active against various DNA viruses Cidofovir has modest in vitro activity against polyomaviruses It should  only  be considered for treatment of BKVN when other interventions have failed  Highly nephrotoxic Cidofovir has been given at dosages ranging from 0.25 to 1 mg/kg every 1 to 3 wk with generally favorable results

73. Quinolone antibiotic  Initially reported to have anti-BKV activity Two randomized trials showed no benefit of Levofloxacin given either prophylactically immediately following transplantation or as treatment for active BKV viremia

74. RITUXIMAB Therapy with the anti-CD20 mAb rituximab was recently reported with promising results. Patients who had BKVN and were treated with rituximab and followed for 17 mo had no graft failure compared with 46% graft loss in the control group

75. Postinfection Monitoring 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. Viremia clears in 7 to 20 wk , but the initial decrease may be delayed by 4 to 10 wk after immunosuppression reduction. If viremia persists, then further reduction of current maintenance therapy, conversion to sirolimus , or addition of leflunomide can be considered

76. Retransplantation In recipients who have advanced kidney disease or who have returned to dialysis from BKV nephropathy, retransplantation has been successful In most cases, transplant nephrectomy and/or studies to confirm no active viral replication have been performed. In the setting of active viremia, viral levels become undetectable within 14 d after preemptive retransplantation with simultaneous allograft nephrectomy despite antibody induction

77. BKV viruria , viremia ,nephropathy , and graft loss can recur. BKV nephropathy is not a contraindication for retransplantation but has recurred in two (12%) of 17 reported recipients. Allograft nephrectomy may not be necessary. In the setting of active viral replication, it seems prudent.

78. Evidence of BKV-specific immunity can be evaluated before retransplantation For preemptive transplantation in recipients of combined organ transplants, for whom reduction in immunosuppression is limited, evidence of no active viral replication or BKV-specific immunity should be determined.

79. BKV Nephropathy and Acute Rejection Reduction in immunosuppression can precipitate rejection in 10 to 30% of recipients Some experts advocate for treating the acute rejection first ( eg , with pulse glucocorticoids) and then subsequently reducing immunosuppression as a second step once the patient has had a clinical response to antirejection treatment ( ie , a decrease in serum creatinine level)   Other experts avoid augmented immunosuppression and favor a reduction in maintenance immunosuppression alone 

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