BK Virus Nephritis after Renal Transplantation
+
Author Affiliations
- Correspondence:
Dr. Sundaram Hariharan, Division of Nephrology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226. Phone: 414-805-9050; Fax: 414-805-9059; E-mail: sharihar@mcw.edu
Abstract
BK virus nephritis is an increasing
problem and is posing a threat to improving renal transplant graft survival.
The pathogenesis of this condition remains to be investigated. Higher
prevalence of BK virus infection in recent years has been correlated with
declining acute rejection rates and the use of potent immunosuppressive agents.
Patients with this infection usually have asymptomatic viremia and/or nephritis
with or without worsening of renal function. The diagnosis of this disease is
based on detecting the virus or its effects in urine, blood, and renal tissue.
In the past, approximately 30 to 60% of patients with BK virus nephritis
developed graft failure. In recent years, the combination of early detection,
prompt diagnosis, and therapies including preventive measures have resulted in
better outcomes.
The term “BK” originated from a
patient's initials, in whom it was first detected in 1971 (1).
The next observed case was published by investigators from the University of
Pittsburgh in 1995 (2).
Since then, there have been numerous reports on BK virus (BKV) infection and
BKV nephritis (BKVN) in renal transplant recipients (3–8).
The factors that lead to its higher incidence in recent years and its
pathogenesis remain poorly understood. Increased awareness, the ability of
clinicians to recognize this infection, and the availability of better
diagnostic tools may be contributing to higher prevalence of this disease in
recent years (9).
The use of potent immunosuppressive combination therapy with mycophenolate
mofetil (MMF) and tacrolimus has been thought to play a role in the occurrence
of this infection (10–12);
however, this infection is also seen with cyclosporine and sirolimus therapy (13).
Prevalence of BK viremia within 1 yr after transplantation is approximately 20%
(6,14)
and is higher than the prevalence of acute rejection of 13% reported for the
year 2003 (15).
This review discusses the pathogenesis, clinical features, therapy, and the
short- and long-term renal graft survival with reference to BKV infection.
Pathogenesis
of BKV Infection
Potential factors that contribute to
the pathogenesis of BKVN may be a combination of (1) ineffective immune
surveillance by the host T lymphocytes, (2) the absence of previous
humoral immunity to BKV, (3) molecular sequence variability of the
virus, and (4) alloimmune activation. These details have been reviewed
elsewhere (9)
and are also discussed next.
Cellular immunity in the development
and clearance of BKV infection has remained an important area of research in
the past several years. Comoli et al. (16)
showed a reduction in BKV-specific IFN-γ–secreting lymphocytes in patients with
BKVN compared with healthy control subjects. The authors noted an increase in
patient IFN-γ–secreting lymphocyte levels with reduction in immunosuppressive
therapy similar to that of their healthy counterparts (16).
Prosser et al. (17)
used an IFN-γ 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-γ activity was noted with resolution of BKVN.
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 (18–25).
Within this body of work, Provenzano et al. (25)
showed that specific sites within the large T antigen p53 binding region
elicited increased CD8+ T cell responses. Chen et al. (19)
showed two epitopes within the VP1 capsid protein that were recognized by
cytotoxic T lymphocytes. These regions were found to be variably recognized in
healthy individuals compared with kidney transplant recipients. 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 (18–25).
Leuenberg et al. (21)
hypothesized that the BKV agnoprotein would also contain epitopes that would
stimulate T cell activity. This hypothesis stemmed from the observation that
viral agnoprotein production is high after infection. Their results, using an
ELISPOT assay, showed little IFN-γ production in both healthy volunteers and
kidney transplant recipients when stimulated by agnoprotein. It is interesting
that they showed no increase in anti-agnoprotein Ig production in patients with
BK viremia. Ig activity against large T antigen and VP1 was increased in
patients with BK viremia compared with healthy control subjects (21).
Humoral immunity may play a role in
the pathogenesis of BKVN because those with previous immunity to BKV may not
develop clinical infection, irrespective of the number of circulating viral
copies. Bohl et al. (26)
found that recipients of a kidney from a seropositive donor were more likely to
develop BK viremia compared with those who received a kidney from a
seronegative donor. Recipient serostatus did not show a statistically
significant difference in viremia, however. In contrast, Smith et al. (27)
found recipient seronegativity to be a significant risk for development of BKVN
(P = 0.01) in a pediatric population. Donor serostatus was not analyzed
because of paucity of data from all donors. Ginevri et al. (28)
showed recipient seronegative status and MMF use at baseline to be predictive
of BKV infection (P < 0.005). In their retrospective analysis of
pediatric renal transplant recipients' donor serostatus, cold ischemia time,
acute rejection history, use of calcineurin inhibitor, and induction agent used
were not contributing factors to posttransplantation BKV infection. The role of
the recipient's humoral immunity to BKV at the time of transplantation and at
viremia to the development of BKVN needs further evaluation.
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. Awadalla et al. (29)
showed that the occurrence of BKVN correlates with a higher degree of HLA
mismatches, which postulates the role of alloimmune activation. Investigators
from Emory University (30)
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. It is interesting that
Drachenburg et al. (31)
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
(P = 0.0.001), thus postulating lack of HLA matches as a predictor of
better outcome in patients with BKVN. The authors speculated that antiviral
immune response is likely to trigger a variety of nonspecific inflammatory and
fibrogenic mechanisms that lead to graft failure, and 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.
In addition, viral entry into
susceptible host cells is an integral component of BKV infection. Eash et
al. (32)
showed that the caveolin-1 scaffolding domain and presence of cholesterol were
required for viral entry into an immortalized primate renal tubular cell line
(Vero). Recently, Moriyama et al. (33)
showed that blockade of caveolin-induced endocytosis, either by direct
inhibitors or via small interference RNA depletion of caveolin-1, caused
significant decreases in BKV infectivity as measured by immunofluorescence.
They also proved that blockade of clathrin-mediated viral entry had no effect
on infectivity. BKV particles were also found to co-localize with caveolin-1,
not clathrin. It therefore seems that BKV entry into its human target cells in
vitro depends on a caveola-dependent pathway. This has potential future
implications regarding therapeutic options in patients with BKV infection.
Thus, the pathogenesis of BKV infection is possibly secondary to a combination
of cellular and humoral immune deficiencies with alloimmune activation as well
as BKV's tropism to renal tubular epithelial cells.
Clinical
Features
Clinical
Presentation
BKVN has increasingly been
recognized as an early event and occurs within the first year after
transplantation (4,6,11,34,35).
Patients with BKVN usually remain asymptomatic and are detected when they
experience renal insufficiency. BKV DNA is detected in the urine and plasma in
nearly all cases of BKVN (35).
Renal dysfunction secondary to ureteric stricture leading to hydronephrosis is
occasionally seen (36),
and severe systemic disease leading to multiorgan failure has been reported (37).
Diagnosis
Decoy cells seen on urine cytology
have been observed in patients with BKVN and originate from infected renal
tubular cells with nuclei altered by viral inclusions. The presence of decoy
cells is a sensitive (100%) measure but has a low positive predictive value of
29% for the diagnosis of BKVN (38).
Overall, it seems that the presence of decoy cells is a good screening test but
not diagnostic of BKVN.
Quantification of viral load in
blood and urine with either viral DNA or mRNA to VP-1 has been used to diagnose
BKVN. Urinary BKV DNA is seen in at least 50% of transplant recipients, but
variability in testing conditions has created difficulty in standardizing this
method for definite diagnosis (39).
Some authors have suggested using urinary VP-1 mRNA load to document active
viral replication (40).
BKV DNA quantification in plasma is used as an important diagnostic tool and is
detected in 15 to 30% of renal transplant recipients during the first
posttransplantation year (6,14).
Quantification of BKV DNA in plasma by PCR has sensitivity and specificity of
100 and 88%, respectively, to BKVN (34,38);
however, not all patients with BK viremia have nephritis (positive predictive
value of 50%) (39).
Higher BKV DNA copy number is associated with an increased likelihood of having
nephritis and has also been correlated with severity of disease (39).
BK V DNA >7000 or 10,000 copies/ml plasma is used by some as a threshold for
significant infection and correlates with BKVN. Nephritis, however, can be seen
with BKV DNA <7000 copies/ml plasma (9,39).
Limaye et al. (41)
reported BKVN in an immunosuppressed nonrenal transplant patient without
detectable viremia. The exact reason for this is unclear, and possibilities
include nonstandardization of BKV DNA estimation leading to variability in
levels of viremia from one laboratory to another. Thus, one should be cautious
in recommending a level of viremia as a threshold for the occurrence of
nephritis.
Pathologic findings of infection
include viral cytopathic changes in the epithelium of tubules, glomeruli, and
collecting ducts with interstitial inflammation and varying degrees of tubular
atrophy or fibrosis (42).
Patchy interstitial involvement is common early in the course of disease followed
by extensive inflammation progressing to fibrosis. Sampling error as a result
of the focal nature of renal involvement does pose a problem in considering
renal histology as a gold standard for the diagnosis of infection (42).
The presence of tubular basement membrane immune deposits (positive C4d
staining) has been seen in some cases and is associated with more severe
disease (43,44).
An additional impediment to diagnosis of BKVN on biopsy specimens is its
similarity to acute rejection. Immunoperoxidase staining for SV40, another
member of the Papovaviridae family, cross-reacts with BKV and highlights
infected tubular cells, suggesting virus-induced inflammation as opposed to
acute rejection (9,35).
Another method used to delineate between acute rejection and BKVN is
immunohistochemical staining of renal tissue or urinary sediment with
anti–HLA-DR, which has been shown to be associated with acute rejection (45–48).
In addition, a higher proportion of CD20+ cells in the infiltrates
in the kidney has been correlated with BKVN as opposed to acute rejection (4).
A renal biopsy grading system for BKVN has been implemented (42).
Biopsies that display minimal or mild viral cytopathic changes are designated
with an A grade; increased inflammation and mild to severe viral cytopathic
changes are given a B grade; and C grade biopsies have moderate to severe
tubular atrophy, interstitial fibrosis, and inflammatory infiltrates (42).
The diagnosis of BKV infection is based on quantification of plasma and/or
urinary BKV DNA with presence of urinary decoy cells in urine cytology with or
without renal histologic features of nephritis.
Treatment
The goal in treating BKV infection
is to eliminate the virus while preserving renal function and preventing acute
or chronic rejection. The treatment of BKV infection has centered on
alterations in immunosuppressive therapy with or without antiviral therapies.
Several regimens for altering immunosuppressive therapy have been attempted to
treat this infection. These include discontinuation of an agent, decreasing an
agent, switching immunosuppressant within the same class or to another class,
and steroid avoidance. As a proof of this strategy, patients who had BKV
infection and were inadvertently treated with an antilymphocyte agent or pulse
corticosteroids for presumptive acute rejection had rapid progression toward
graft failure (6,49).
Discontinuation of a single
immunosuppression agent, antimetabolite (MMF or azathioprine), upon recognition
of viremia has been used successfully to clear viremia (49).
Reduction in immunosuppression by halving both antimetabolites and calcineurin
inhibitors has also been successful in eliminating viremia and preserving renal
function (50).
Steroid avoidance has been suggested to decrease the prevalence of BKV
infection (51).
Antiviral therapy with leflunomide
or cidofovir has been used in conjunction with decreasing immunosuppression in
some cases. Leflunomide is an immunosuppressant medication developed for use in
treatment of rheumatoid arthritis. A metabolite of leflunomide (A77 1726) has
been shown to have antiviral properties (52,53).
Treatment with this agent is associated with decreasing circulating viral
copies (53–55);
however, introduction of leflunomide has been attempted only with concomitant
discontinuation of the antiproliferative agent MMF and decreased dosages of
tacrolimus (53,54).
Hence, it is unclear whether viral clearance is secondary to leflunomide or the
decrease in immunosuppression. 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 (53–55).
In their successful report of 17 patients with BKVN, Williams et al. (53)
showed viral clearance or reduction in viral load when A77 1726 levels
persisted above 40 μg/ml. This requirement for a target therapeutic level of
leflunomide was confirmed by the same investigators in their subsequent study
of 26 patients with BKVN (54).
A short-acting leflunomide, FK778, has been compared with reduction in
immunosuppression alone in a prospective, randomized study to treat BKVN. This
study did not show any beneficial effect of FK778 in clearing the virus as
opposed to reduction in immunosuppression alone (A. Guasch, Department of
Medicine, Emory University School of Medicine, Atlanta, Georgia, personal
communication (May 9, 2007 at the American Transplant Congress), presented for
Astella Study Group ATC 2007).
Cidofovir, a nucleoside analogue
used in the treatment of cytomegalovirus retinitis, has shown activity against
BKV. Unfortunately, cidofovir is nephrotoxic, and its use must be weighed
against the possible risk for further worsening of renal function (56–58).
Cidofovir has also been used in conjunction with lowering immunosuppression,
making comments regarding its efficacy difficult. A prospective, randomized,
controlled trial is under way to evaluate the efficacy and safety of cidofovir
for patients with BKVN (http://www.clinicaltrials.gov/ct2/show/NCT00138424).
Cidofovir is administered when patients fail to respond to reduction in
immunosuppressive therapy and is administered typically 10 to 20% of that
needed in the treatment of cytomegalovirus retinitis in patients with HIV
infection (0.25 to 1 versus 3 to 5 mg/kg) (57,58).
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 (59).
The administration of intravenous Ig (IVIG) with concomitant reduction in
immunosuppressive therapy has been successful; however, efficacy of IVIG is
unclear, because it has been administered with concomitant reduction in
immunosuppressive therapy (54,60).
Wadei et al. (61)
recently reported on their experience with treatment of BKVN with cidofovir and
IVIG in patients whose immunosuppression was generally reduced in all and
converted to cyclosporine therapy in some. Their findings suggested no benefit
with conversion to cyclosporine from tacrolimus, use of cidofovir, or IVIG
therapies.
Close monitoring for BKV DNA and
renal function with any therapy is critical to improving outcome for patients
with BKV infection. Elimination of BKV DNA occurs during a period of 6 mo with
either an antiviral agent or reduction in immunosuppressive therapy (50,53).
At our center, we follow quantitative plasma BKV DNA and renal function every 2
wk for 8 wk then monthly thereafter until clearance of BK viremia and
stabilization of renal function. We have been successful in eliminating
circulating virus and preventing further renal dysfunction with low rates of
acute rejection (50).
Thus, close follow-up is of paramount importance in effectively treating
patients with BKVN.
Prevention
Inability to pinpoint the
pathogenesis of BKV infection and lack of safe and effective antiviral therapy
has prompted investigators to consider a preventive approach in managing this
disease. Preventive strategies include identification of this disease by
detecting BKV DNA in blood or urine and preemptive reduction in
immunosuppression for patients with viremia or viruria. Higher prevalence of
viruria, as opposed to viremia, and lack of good correlation with viruria have
prompted investigators to use viremia as a better marker for preemptive
reduction in immunosuppressive therapy. Vigorous posttransplantation screening
and preemptive reduction in immunosuppressive therapy have decreased the
prevalence, detected disease at an early stage, and improved graft survival of
patients with BKVN at our center (62).
Multiple authors have recommended a
step-wise approach to screening for BKV infection. Hirsch et al. (39)
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 (62).
Buehrig et al. (63),
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 (63).
More recently, Khamash et al. (64)
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.
A strategy for preemptive decrease
in immunosuppression is backed by data suggesting that the presence of viruria
predates viremia, which in turn predates the detection of clinical renal
disease and histologic evidence of BKVN (14,34,38,65,66).
Preemptive reduction in immunosuppressive therapy for those with significant
viremia has substantially lowered the prevalence of BKVN at our center (62).
Thus, detection of early disease and modification immunosuppressive therapy are
effective in treating this infection.
Risk
Factors for the Occurrence of BKVN
Various risk factors for the
occurrence of BKVN are shown in Table 1.
These include donor–recipient-specific humoral immunity, alloimmune activation,
and immunosuppressive agents. Before 1995, BKVN was rarely identified, and MMF
and tacrolimus were introduced at approximately the same period for clinical
transplantation; however, occurrence of BKVN does not seem to be limited to the
use of specific immunosuppressive agents but may be related to overall degree
of immunosuppression. Brennan et al. (14)
prospectively evaluated differences in viremia and viruria with three
immunosuppressive combination therapies. Viruria was highest with
tacrolimus-MMF combination (46%) compared with cyclosporine-MMF (13%) therapy,
but the choice of calcineurin inhibitor or adjuvant immunosuppression did not
influence viremia or nephritis.
View this table:
Table 1.
Risk factors for the development of
BKVN after renal transplantationa
Shi et al. (12)
showed significant higher occurrence of BKVN with the use of 15-deoxyspergualin
to treat acute rejection (57.1 versus 3.7%; P < 0.001). They
also found an increased risk with the combination of tacrolimus and MMF therapy
(P = 0.003). Thus, risk factors such as HLA mismatches, use of
tacrolimus-MMF immunosuppression, and BKV-specific immune deficiencies have
been identified.
Short-
and Long-Term Graft Survival
In the late 1990s and early 2000s,
BKVN resulted in irreversible graft failure in 30 to 60% of cases. This
occurred because of lack of awareness, misdiagnosis, late diagnosis, and
inadvertent use of intensive immunosuppressive therapy for presumptive acute
rejection (4,6).
The actuarial kidney graft survival
for patients with BKVN has improved in the past decade. The 1-, 3-, and 5-yr
actuarial kidney graft survival for patients with BKVN at our center (n
= 58) was 94.8, 68.4, and 57.6%, respectively (62).
This is substantially better than our earlier series of 89.5, 57.9, and 47.4%,
respectively (67).
This is due either to early detection of viremia and resolution of viremia with
therapeutic intervention to prevent the occurrence of nephritis or to detection
of minimal histologic changes of nephritis during routine surveillance biopsy.
In recent years, transplant patients with viremia are submitted for renal
biopsy, leading to diagnosis of subclinical nephritis without renal
dysfunction. Thus, bias toward early diagnosis may be influencing better graft
survival in recent years. Treatment strategies have shown significant
short-term improvements, such as elimination of circulating viremia; however,
long-term events, such as late acute and chronic rejections, need to be
investigated.
Repeat transplant can be performed
successfully after primary graft failure secondary to BKVN (68,69).
Ramos et al. (69)
reported successful repeat transplantation in nine of 10 patients without
recurrent BKVN. Womer et al. (68)
recently reported successful repeat transplantation in two patients despite
active viremia. Transplant graft nephrectomy has been advocated and seems
prudent before repeat transplantation to eliminate the graft that is infected
with BKV; however, there is no evidence to support this practice. Regardless,
the risk for recurrent BKVN after second transplantation is possibly real and
should not be ignored.
Conclusions
BKV infection is an important
clinical problem in kidney transplant recipients and is most likely due to the
enhanced immunosuppressive state and BKV-specific immune deficiency with
alloimmune activation. Using diagnostic tools such as BKV DNA in urine and or
plasma and careful renal histologic evaluation are critical to making the
diagnosis. More important, therapy with reduction in immunosuppression and/or
antiviral therapy with careful monitoring of patients with BKVN is of paramount
importance to prevent progressive renal graft failure. Screening for viremia or
viruria can be used to identify early infection, and preemptive reduction in
immunosuppression for patients with viremia can decrease the prevalence of
BKVN. In recent years, early diagnosis, prevention, and prompt treatment of BKV
infection have improved short- and long-term graft survival.
Disclosures
None.
- Copyright © 2008 by the American Society of Nephrology
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- Abstract
- Pathogenesis of BKV Infection
- Clinical Features
- Treatment
- Prevention
- Risk Factors for the Occurrence of BKVN
- Short- and Long-Term Graft Survival
- Conclusions
- Disclosures
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This
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- doi: 10.2215/CJN.02770707 CJASN March 2008 vol. 3 no. Supplement 2 S68-S75
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- Pathogenesis of BKV Infection
- Clinical Features
- Treatment
- Prevention
- Risk Factors for the Occurrence of BKVN
- Short- and Long-Term Graft Survival
- Conclusions
- Disclosures
- References
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