BKV INFECTION

2.  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.  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.  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.  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.  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.  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.  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

30.  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

31.  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

32.  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)

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

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

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

36.  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

37.  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

38.  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.

39.  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.

40.  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

41.  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

42.  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

43.  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.

44.  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

45.  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.

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

48.  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.

49.  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

50.  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

53.  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."

54.  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.

55.  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

58.  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.

59.  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

60.  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

61.  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)

62.  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

63.  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

64.  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

65.  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

67.  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.

68.  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

69.  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

70.  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.

71.  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

72.  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

73.  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

75.  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

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

77.  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

78.  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

79. 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

80.  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

82.  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

83.  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

84.  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.

85.  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.

86.  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