BK nephropathy in kidney transplant recipients treated with a calcineurin inhibitor-free immunosuppression regimen.
ABSTRACT Recently, polyomavirus-associated nephropathy (PVAN) has been reported more frequently and is emerging as an important cause of renal allograft dysfunction and graft loss. Susceptibility appears to be related to the type and intensity of pharmacologic immunosuppression but some reports have suggested a link among the development of PVAN, the treatment of rejection or maintenance with a tacrolimus-based immunosuppressive regimen. We report three cases of PVAN in patients who never received immunosuppression with calcineurin inhibitors (CNIs). Two patients received induction immunosuppression consisting of an IL-2 receptor antagonist while 1 received thymoglobulin. These 3 patients were maintained on prednisone, sirolimus and mycophenolate mofetil (MMF) and none was treated for rejection. All three patients presented with an elevated serum creatinine and demonstrated polyomavirus infection on biopsy and by blood PCR. These cases demonstrate that, unlike reports linking tacrolimus and PVAN, polyomavirus infection may develop in patients maintained on CNI-free immunosuppressive regimens and have not had episodes of rejection.
- SourceAvailable from: Josefina AlberuRevista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion 04/2005; 57(2):213-224. · 0.31 Impact Factor
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ABSTRACT: BACKGROUND: The study evaluated the relationship of pretransplantation BK virus (BKV)-specific donor and recipient serostatus to posttransplantation BKV infection. METHODS: Two hundred forty adult de novo kidney-only recipients and 15 pediatric recipients were prospectively enrolled and followed for a minimum of 18 months. Pretransplantation BKV serostatus was available for 192 adult and 11 pediatric donor-recipient pairs. Based on BKV-specific IgG enzyme immunoassay ≥8 units, subjects were divided into four groups: D+R+, D+R-, D-R+, and D-R-. BKV DNA surveillance was performed at 1, 3, 6, 12, and 24 months. The outcomes studied were development of any BKV infection, viremia, and significant viremia (≥10,000 copies/mL plasma). RESULTS: Of the 192 adult subjects (D+R- [n=41], D+R+ [n=42], D-R+ [n=41], and D-R- [n=68]), 89 of 192 developed any BKV infection and 62 of 89 developed BK insignificant viremia (n=33) and significant viremia (n=29). Any BKV infection developed in 25 of 41, 22 of 42, 17 of 41, and 25 of 68 in the D+R-, D+R+, D-R+, and D-R- groups, respectively. Any viremia (20 of 41) and significant viremia (10 of 41) seen in the D+R- group was significantly higher than other groups (P=0.014). In 11 pediatric recipients, infection was seen only in the D+R- group. Overall, infection was highest in the D+R- group and lowest in the D-R- group. CONCLUSIONS: BKV serostatus can be used to risk stratify patients for posttransplantation infection.Transplantation 03/2013; 95(6):896-902. · 3.78 Impact Factor
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ABSTRACT: Overimmunosuppression is a widely recognized risk factor for BK virus (BKV) infection, particularly with the combination of tacrolimus, mycophenolate mofetil (MMF), and steroids. Nevertheless, the exact impact of exposure to tacrolimus and MMF is not well understood. We examined 240 kidney recipients between 2006 and 2008. BKV was monitored every 2 months in the urine or blood. A kidney biopsy was performed when viremia exceeded 10 copies/mL. Ninety-five (40%) patients had sustained viruria, 48 (20%) sustained viremia, and 17 (7%) biopsy-proven polyomavirus-associated nephropathy. The mean time-to-occurrence was 7.6, 7.9, and 9.7 months for viruria, viremia, and polyomavirus-associated nephropathy. Risk factors associated with BKV infection in univariate analyses were retransplantation, panel-reactive antibody more than 0%, cytomegalovirus D+/R-, cold ischemia time, delayed graft function, induction with antithymocyte globulins, acute rejection before month 3 (M3), tacrolimus trough levels more than 10 ng/mL, and M3 AUC0-12 hr more than 50 hr mg/L. Multivariate analyses showed that cytomegalovirus D+/R- (adjusted hazard ratio [AHR], 2.03; P=0.05), acute rejection (AHR, 5.4; P<0.001), and mycophenolic acid AUC0-12 hr more than 50 hr mg/L (AHR, 3.6; P=0.001) were risk factors for BKV. This study identified a link between a state of increased immunosuppression and BKV infection, especially in patients with higher MMF exposure and elevated tacrolimus trough levels at M3.Transplantation 06/2013; 95(12):1498-505. · 3.78 Impact Factor
American Journal of Transplantation 2004; 4: 2132–2134
Copyright C ?Blackwell Munksgaard 2004
BK Nephropathy in Kidney Transplant Recipients
Treated with a Calcineurin Inhibitor-Free
Gerald S. Lipshutza,∗, Stuart M. Flechnerb,
Mahendra V. Govanicand Flavio Vincentia
aUniversity of California, San Francisco, Department of
Surgery, San Francisco, California, USA
bCleveland Clinic Foundation, Glickman Urological
Institute, Cleveland, Ohio, USA
cIndiana University Hospital, Division of Nephrology,
Indianapolis, Indiana, USA
∗Corresponding author: Dr. Gerald S. Lipshutz,
(PVAN) has been reported more frequently and is
emerging as an important cause of renal allograft
dysfunction and graft loss. Susceptibility appears
to be related to the type and intensity of pharma-
cologic immunosuppression but some reports have
suggested a link among the development of PVAN,
the treatment of rejection or maintenance with
We report three cases of PVAN in patients who
never received immunosuppression with calcineurin
inhibitors (CNIs). Two patients received induction
immunosuppression consisting of an IL-2 receptor
antagonist while 1 received thymoglobulin. These 3
patients were maintained on prednisone, sirolimus
and mycophenolate mofetil (MMF) and none was
treated for rejection. All three patients presented
with an elevated serum creatinine and demonstrated
polyomavirus infection on biopsy and by blood PCR.
These cases demonstrate that, unlike reports linking
tacrolimus and PVAN, polyomavirus infection may
develop in patients maintained on CNI-free immuno-
suppressive regimens and have not had episodes of
cineurin Inhibitor, Sirolimus
Received 17 April 2004, revised and accepted 29 June
Polyomavitus, BK nephropathy, Cal-
Polyomavirus infection in kidney transplant recipients
has emerged as an important cause of renal allograft
loss. Infection in the transplanted kidney may result
in non-anastomotic ureteral strictures or in tubulointer-
stitial nephritis compromising kidney allograft function
and ultimately resulting in loss. Polyomavirus-associated
nephropathy (PVAN), caused by BK virus (BKV), may be
diagnosed by immunohistochemistry, in situ hybridization,
PCR for polyoma virus from blood, urine and transplant
biopsy tissue and the detection of decoy cells in urine (1–
5). Recently there has been an increase in the reported
incidence of PVAN, due to several reasons. Improvement
in screening methods has allowed for differentiation of
PVAN from allograft rejection (6). In addition, some have
suggested that the development of more potent immuno-
suppression has led to an increase in the prevalence of
PVAN. Some reports have suggested that PVAN is linked
to the use of immunosuppression regimens containing
tacrolimus (6–8). However, PVAN has not been exclusive
to patients who received tacrolimus as it has been seen in
patients maintained on the other calcineurin inhibitor (CNI),
cyclosporine. Others believe it is related to a state of gen-
eral overimmunosuppression (9).
The purpose of the present communication is to report
the development of three cases of PVAN in patients who
had not received CNIs as part of their immunosuppressive
regimen. In part we hope that this will serve to support
the concept that the risk of PVAN is not associated with
a single immunosuppressive agent but instead with the
overall state of immunosuppression.
A 68-year-old native American female with end-stage renal disease sec-
ondary to hypertension presented for a deceased donor kidney transplant.
Her CMV serology was D+R+. The donor and recipient were matched at
1 HLA locus. In the operating room she received 500 mg of methylpred-
nisolone and 91 mg of daclizumab. On post-operative day 4, the patient was
discharged with a creatinine of 4.3 mg/dL. Discharge immunosuppression
consisted of a prednisone taper, mycophenolate mofetil (MMF) 1000 mg
b.i.d. and sirolimus 5 mg/day. On follow-up 4 days later, the patient’s serum
creatinine was 2.0 mg/dL and 3 months later 0.9 mg/dL.
Three and a half months after transplantation, she presented with a serum
creatinine of 1.9 mg/dL and an ultrasound demonstrated hydrouteronephro-
sis. She had not suffered any episodes of rejection during this time. Im-
munosuppression consisted of prednisone 5 mg/day, MMF 250 mg b.i.d.
and sirolimus 3 mg/day (level 11.5 ng/mL; target range 8–15 ng/mL). A
BK Nephropathy in Kidney Transplant Recipients
pyelogram demonstrated a narrow stricture proximal to the ureterovesical
junction. Urine PCR for BKV was 7.1 × 107DNA copies/mL. Repeat urine
PCR for BKV 2 weeks later demonstrated 1.1 × 107copies/mL while PCR
from blood demonstrated 5.7 × 104copies/mL (quantitative PCR for all
specimens performed by Viracor, Lee’s Summit, MO). A kidney transplant
sistent with polyoma virus infection. The patient’s immunosuppression was
changed to microemulsion cyclosporine and prednisone. Three weeks later
the patient’s creatinine peaked at 4.9 mg/dL. Intravenous cidofovir was be-
when urine BKV was 1.1 × 108copies/mL with PCR of the blood demon-
strating 1.7 × 104copies/mL. The patient began to respond 3 weeks later
to 9.6 × 103copies/mL. Two and a half months after beginning therapy and
immunosuppression reduction, blood BKV declined to 2.1 × 103copies/mL
and became undetectable 2.5 months later.
tic kidney disease received a live donor kidney transplant from his nephew.
His CMV serology was D−R+. The donor and recipient were matched
at 3 HLA loci. In the operating room he received 500 mg of methylpred-
nisolone and 20 mg of basiliximab. He received a second dose of 20 mg
of basiliximab on the 4th post-operative day. His course was unremarkable
and he was discharged on a prednisone taper, MMF 1000 mg b.i.d. and
sirolimus 5 mg/day. His sirolimus was concentration controlled to 10–12
ng/mL the first 6 months. His serum creatinine was 1.3 mg/dL after the first
month. During the 4th month he grew 3000 copies/mL of CMV from whole
blood, which cleared after valganciclovir, and was undetectable 2 months
Between 6 and 8 months after the transplant, the patient experienced an
elevated serum creatinine of 1.8–2.3 mg/dL, and two renal biopsies were
Banff borderline (10). At month 10, a third biopsy demonstrated tubular nu-
clear enlargement, BKV by in situ hybridization and over 2 × 105copies/mL
of BKV was detected from the blood by quantitative PCR (performed by
Focus Technologies, Cypress, CA). Immunosuppression was reduced to
sirolimus 2 mg/day and prednisone 5 mg/day, and the patient was treated
with biweekly doses of cidofovir for 3 months (0.33 mg/kg dose without
probenecid). The treatment was not successful, renal function deteriorated
and he returned to hemodialysis 14 months after transplantation. After cido-
at its peak (3 × 106copies/mL). Two months later, and after discontinuing
immunosuppression, blood BKV declined to 7.6 × 102copies/mL.
A 61-year-old African American male with end-stage renal disease sec-
ondary to focal segmental glomerulosclerosis presented for a deceased
donor kidney transplant. His CMV serology was D−R+. The donor and re-
cipient were matched at 2 HLA loci. The graft was initially slow to function
but the recipient did not require hemodialysis. He was given 3 doses of thy-
moglobulin (1.5 mg/kg per dose) on post-transplant day 0, 2 and 4. Methyl-
prednisolone 500 mg was introduced on day 0 and tapered to prednisone
20 mg/day by day 4. He was also given MMF 1500 mg b.i.d. starting on
day 0. Sirolimus 4 mg/day was started on day 1 and the trough level was
maintained at 10–15 ng/mL. On day 5, his serum creatinine was 3.5 mg/dL
and he was discharged home. His serum creatinine stabilized at 2.3 mg/dL.
Five months later a biopsy was performed for a rising serum creatinine
(3 mg/dL) and BKV was diagnosed by intranuclear inclusions on microscopy
and positive staining for SV40 T antigen on immunohistochemistry. His im-
munosuppression was sirolimus 7 mg/day (trough level 11.8 ng/mL), MMF
1000 mg b.i.d. and prednisone 10 mg/day. Blood and urine were also posi-
by Viracor, Lee’s Summit, MO). Sirolimus was discontinued and prednisone
was increased to 20 mg/day. The patient’s serum creatinine decreased to
2.4 mg/dL after 3 weeks. One month later, he developed a CMV infection
characterized by fever, generalized weakness and malaise. CMV antigen
was positive in 310 out of 300 000 leukocytes, which was successfully
treated with ganciclovir.
One year after the transplant, the patient has continued to do well with a
serum creatinine at baseline (2.2 mg/dL). He does not have viremia but has
low-level viruria (1.3 × 104copies/mL). He is maintained on MMF 1000 mg
b.i.d. and prednisone 5 mg/day.
PVAN has been associated with early graft loss following
kidney transplantation. It is generally of low incidence (1)
but the diagnosis has been increasing recently (11). A re-
lationship between this increase in incidence and the use
of more potent immunosuppressive agents appears likely.
Since these agents have greatly reduced the rates of acute
cellular rejection, as a consequence they may have cre-
ated an environment that increases the incidence of poly-
omavirus reactivation (1,12). It is, however, more likely that
specific immunosuppressant agent that is responsible for
the development of PVAN.
Reports have concluded that PVAN is linked to the use
8), and not just to a state of overimmunosuppression (9).
Some have suggested this relationship because the inci-
dence of BKV nephropathy appeared to increase after the
by some, may instead simply represent the widespread
use of tacrolimus in most transplant centers today (13). It
is generally believed that tacrolimus has greater immuno-
suppressive efficacy than cyclosporine. However, no study
has in fact addressed this in a controlled manner. In a re-
cent report (14), though, a randomized study of 50 kid-
ney transplant patients were evaluated prospectively after
treatment with either tacrolimus or cyclosporine, the au-
thors found no difference in the incidence of polyoma virus
infection between the two groups during 36 weeks after
transplantation. Currently, a large worldwide-randomized
trial of cyclosporine versus tacrolimus (the DIRECT Trial) is
being conducted; it will assess the risk of developing BKV
infection as one of its endpoints.
Regardless of whether tacrolimus or cyclosporine plays a
greater role, the patients described in this series did not
receive any CNIs as part of their immunosuppressive reg-
imen and thus evidence to suggest a causal link between
CNIs and the development of BKV nephropathy appears
to be lacking. A fourth case does exist in the literature
(15). In a multicenter trial initiated at the Mayo clinic, one
patient in one arm of a cyclosporine avoidance trial uti-
lizing sirolimus, MMF and steroids (after Thymoglobulin
American Journal of Transplantation 2004; 4: 2132–2134
Lipshutz et al.
induction), also developed BKV nephropathy (15). Whether
the development of PVAN with the combination of MMF
and sirolimus is a reflection of the immunosuppression in-
tensity of this regimen or the result of the additive effects
of two antiproliferative agents is unclear.
Other risk factors may play a role in the development of
PVAN, such as the number of HLA mismatches (3), which
may decrease the efficiency of MHC-linked antiviral immu-
recipients who were male (11,17) and older (11). Additional
risk factors may include the presence of CMV disease as
BKV has the potential to increase the amount of regulatory
in patients have been conflicting.
The surgical techniques of transplantation result in warm
ischemia, reperfusion injury and acute tubular necrosis re-
sulting in the release of proinflammatory cytokines, cellu-
lar injury and expression of virus-specific cell surface re-
ceptors (16) all promoting an invasive viral state. However,
one report found no statistically significant relationship be-
tween allograft type (deceased or living donor) or duration
of cold ischemia and PVAN (3). In the present report, 2 out
of 3 patients were male, all were older than 60, the aver-
age HLA mismatch rate was high (4 loci) and 2 developed
CMV disease. Together these factors along with general
pharmacologic immunosuppression, not related to a single
immunosuppressive agent, may have played a combined
role in the development of PVAN.
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American Journal of Transplantation 2004; 4: 2132–2134