Screening and Treatment Strategies
for BK Virus in Kidney Transplant
Recipients
David Wojciechowski
UCSF Kidney Transplant Service
Discovery of Human
Polyomaviruses
*SV40: simian virus introduced to the population through contaminated polio and
adenovirus vaccines
Risk Factors
Dall et al. BK virus nephritis after renal transplantation. Clin J Am Soc Nephrol 2008; 3:
S68-S75.
Pathogenesis


Diminished immune
response
Uroepithelial injury




Ischemia
Ureteral stent
Rejection
Donor BKV*
Lysis of tubular cells releases
BKV into tubules with bare
basement membranes.
Virus particles can leak into the
interstitium; the virus gains
access to capillaries: viremia
results.
BKV Natural History
78 renal tx recipients prospectively followed
30%
16Wks
13%
23Wks
8%
28Wks
Hirsch et al. Prospective study of polyomavirus type BK replication and nephropathy in renal transplant recipients. N Engl
J Med 2002; 347: 488:96.
Screening: KDIGO Guidelines
Treatment of BKV
Treatment of BK Viremia
Reduction of immunosuppression!
Treatment of BK Viremia
 Prospective
study of 200 new renal
transplant recipients
 23 developed BK viremia
 Anti-metabolite was stopped
 If viremia failed to clear after 4 weeks CNI
dose was reduced (CSA trough of 100-200
ng/ml; TAC trough of 3-5 ng/ml)
Brennan et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction.
AJT 5: 582-594, 2005.
Treatment of BK Viremia
 22/23
(95%) cleared viremia by 1 year
post-transplant
 Mean time to clearance was 54 days
 1 patient developed acute rejection related
to immunosuppression reduction
 No patients developed BK nephropathy
Brennan et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction.
AJT 5: 582-594, 2005.
Treatment of BK Viremia


No BK nephropathy identified on cause biopsies
No new BK viremia after month-12

Only checked on patients undergoing a cause biopsy
Hardinger et al. BK-Virus and the Impact of Pre-Emptive Immunosuppression Reduction: 5-Year Results. AJT
2010; 10: 407-415.
BK Nephropathy Treatment
 First-step:
Immunosuppression Reduction
 Second-step: Active therapy

Anti-Viral Agents
• Leflunomide
• Cidofovir
• Fluoroquinolones

IVIG
Leflunomide
 Leflunomide


Metabolized to A77 1726
Inhibits dihydroorotic acid dehydrogenase
(necessary for de novo pyrimidine synthesis)
and tyrosine kinases involved in T and B cell
signaling cascades
 MOA

against BK unclear
May inhibit viral assembly
Leflunomide







26 patients with biopsy proven BKVAN (mean
time to diagnosis 15.4 months post-transplant)
MMF stopped
TAC trough target 4-6 ng/ml
Prednisone 5-10 mg/day
Leflunomide started with a loading dose of 100
mg/day for 5 days
Leflunomide maintenance dose: 40 mg/day
(target trough 50-100 µg/ml)
*Cidofovir could be added at the discretion of the
treating physician
Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation 2006; 81: 704-710.
In Vitro Data
Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation 2006; 81: 704710.
Leflunomide
Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation 2006; 81:
704-710.
Leflunomide
 Repeat
biopsies in 16 patients ≥4 weeks
after initial biopsy
 4 had no evidence of SV40 staining
 8 had significantly reduced SV40 staining
 2 had persistent or worse staining (neither
pt had A77 1726 blood level >35 at time of
repeat bx)
 Follow-up of 6-40 months graft loss 4/26
(15%)
Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation 2006; 81: 704-710.
Cidofovir

Nucleotide analogue of cytosine active against a
wide array of DNA viruses

Use limited by renal toxicity (accumulates in
RTC causing apoptosis and ARF)

Given at 10-20% of that needed for the
treatment of CMV (0.25-1 mg/kg)
Cidofovir





Prospective, non-randomized trial, biopsy proven BKVAN
Cidofovir dosed at 1 mg/kg for a maximun duration of 10 weeks
Immunosuppression reduction also employed
No significant difference in BK viremia between groups
5/41 experienced acute rejection

4/26 (15.4%) cidofovir; 1/15 (6.7%) no cidofovir
Kuypers et al. A single-centre study of adjuvant cidofovir therapy for BK virus interstitial nephritis in renal allograft recipients. J
Antimicrob Chemother 2009; 63: 417-419.
Fluoroquinolones



Inhibit bacterial DNA replication by targeting the
enzymes gyrase and topoisomerase IV
Inhibit helicase activity of SV40 T-antigen in
vitro1
Two conflicting studies:

1) 10 day course of gatifloxacin in 10 patients with
active BKV replication2
• 70% had reduction in viremia by >80% or disappearance of
detectable urinary decoy cells

1Ali
2) No improvement in viral clearance in 4 patients
after a 10 day course of ciprofloxacin3
SH et al. Inhibition of Simian virus 40 large T antigen helicase activity by fluoroquinolones. Antivir Ther 2007; 12:1.
2Chandraker
A, et al. Use of fluoroquinolones to treat BK infection in renal transplant recipients [Abstract]. AJT 2004; 4:587.
3Thamboo TP et al. Urine cytology screening for polyoma virus infection following renal transplantation: The Oxford experience. J Clin
Pathol 2007; 60: 927-930.
Fluoroquinolones
Gabardi et al. Evaluation of Fluroquinolones for the Prevention of BK Viremia after Renal Transplantation. CJASN 2010.
Fluoroquinolones
Recipient Age, years
(SD)
Recipient gender, male,
n (%)
Recipient race, n (%)
Caucasian
African American
Others
ESRD, n (%)
Diabetes
Hypertension
GN
PCKD
Other
Donor Type, n (%)
Deceased
Living
Ureteral stent at time of
transplant, n (%)
HLA mismatches, mean
(SD)
PRA, mean (SD)
Group 1 (n=106)
53.1 (12.4)
Group 2 (n=130)
50.4 (13.8)
P-value
0.33
64 (60.4)
81 (62.3)
0.76
Month 3
0.16
38 (35.8)
11 (10.4)
57 (53.8)
39 (30.0)
25 (19.2)
66 (50.8)
Viremia
Viruria
Group 1
Group 2
Estimated Estimated
Risk
Risk
Risk
Difference
95% CI
P-value
0.161
0.303
0.065
0.146
0.096
0.157
0.007-0.184
0.043-0.271
0.0378
0.0067
0.238
0.361
0.161
0.230
0.077
0.131
-0.039-0.192
0.002-0.261
0.1982
0.0549
0.263
0.395
0.217
0.323
0.046
0.072
-0.082-0.175
-0.069-0.214
0.4782
0.3470
0.297
0.437
0.261
0.389
0.036
0.048
-0.101-0.174
-0.099-0.197
0.6061
0.5363
Month 6
0.14
Viremia
Viruria
33 (31.1)
20 (18.9)
18 (17.0)
10 (9.4)
25 (23.6)
34 (26.2)
27 (20.8)
39 (30.0)
10 (7.7)
15 (11.5)
64 (60.4)
42 (39.6)
77 (59.2)
53 (40.8)
10 (9.4)
4.2 (1.7)
13 (10)
3.9 (1.9)
0.89
0.21
10.5 (26)
17.4 (30.7)
0.07
Month 9
0.86
Viremia
Viruria
Month
12
Viremia
Viruria
Wojciechowski et al. Ciprofloxacin prophylaxis in kidney transplant recipients reduces BK virus infection at 3 months
but not at 1 year. Transplantation 2012 (In Press).
Figure 1: Kaplan‐Meier plot of proportion of patients with BK viremia and viruria during the first 12‐months post‐transplantation.
P= 0.4058
%
Wojciechowski et al. Ciprofloxacin prophylaxis in kidney transplant recipients reduces BK virus infection at 3
months but not at 1 year. Transplantation 2012 (In Press).
Treatment: IVIG
 Contains
polyomavirus-reactive antibodies
 Retrospective study of 8/216 renal
transplant recipients who developed
biopsy proven BKVAN and BK viremia
 All underwent reduction of
immunosuppression by 50%
 IVIG given at 2g/kg divided over 2-5 days
Sener A, et al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft
recipients. Transplantation 2006; 81:117-120.
Treatment: IVIG


5/8 patients cleared viremia
One graft loss
Sener A, et al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal
allograft recipients. Transplantation 2006; 81:117-120.
Anti-Viral Summary
Hilton R and Tong CYW. Antiviral therapy for polyomavirus-associated nephropathy after renal transplantation. Journal of
Antimicrobial Chemotherapy 2008; 62: 855-859.
Future Directions


Sirolimus + Leflunomide
In vitro reduced large T antigen expression and
BK DNA replication
Liacini et al. Anti-BK Virus Mechanisms of Sirolimus and Leflunomide Alone and in Combination: Toward a New
Therapy for BK Virus Infection. Transplantation 2010; 90: 1450-1457.
Screening/Treatment Summary
Thank You!
Questions???