Risk factors for BK virus infection in era of Therapeutic Drug

Risk factors for BK virus infection in era of
Therapeutic Drug Monitoring
Mémoire présenté à Dijon le 3 février 2011
Pour obtenir le Diplôme d’Etudes Spécialisées de Néphrologie Par Claire BORNI-DUVAL Née le
22/01/1983 à Strasbourg (Bas-Rhin)
Service de Néphrologie-Transplantation Hôpitaux Universitaires de Strasbourg
Directeurs de mémoire : M. le Pr. Bruno MOULIN Et Mme le Dr Sophie CAILLARD
Abstract :
BK virus (BKV) infection is a well-known cause of graft lost in kidney transplantation since
the late 1990s and is still a challenge because of the lack of proven antiviral treatment.
Therefore, precise identification of risk factors should reduce the risk of BKV reactivation
and prevent the polyomavirus associated nephropathy (PyVAN). Overimmunosuppression is
a widely recognized risk factor, in particular the association of tacrolimus, mycophenolate
mofetil (MMF) and steroids. Nevertheless, the precise impact of tacrolimus and MMF
exposure is not well studied.
For this purpose, we included retrospectively 240 kidney or SKP recipients transplanted
between 01/01/2006 and 31/12/2008 in our center. The follow-up ranged from 16 to 60
months (median 3.2 years). BKV was monitored by urine PCR every 2 months during the first
two years and then every 6 months. When viruria exceeded 106 copies/ml or in case of graft
dysfunction, PCR was tested in blood. A kidney biopsy was done when viremia was higher
than 104 copies/ml. Clinical and biological data were collected at month 3, month 12 and
annually thereafter, particularly MMF and CNI drug monitoring.
One hundred and sixteen patients had BK viruria (48%), 95 had sustained viruria (40%), 65
had a high-level viruria (27%), 60 had BK viremia (25%), 48 had sustained viremia (20%)
and 17 had proven-biopsy PyVAN (7%). Mean time of occurrence was 2.9 months for viruria,
3.9 months for viremia and 4.6 months for PyVAN. In univariate analysis, risk factors
associated with BKV infection were: retransplantation (p<0,001 for viruria, p=0.016 for
viremia); PRA>0% (p=0.03 for viruria, p=0.04 for viremia and p=0.01 for PyVAN); cold
ischemia time (p=0.01 for PyVAN); delayed graft function (p=0.038 for viruria, p=0.02 for
viremia); thymoglobulin (p=0.05 for high-level viruria, p=0.02 for viremia); acute rejection
during the first three months (p=0.008 for viruria, p<0.001 for viremia, p=0.004 for PyVAN);
tacrolimus (p=0.0013 for viruria, p=0.01 for viremia and p=0.008 for PyVAN); tacrolimus
trough levels > 10 ng/mL (p=0.02 for viruria, p=0.03 for viremia and p=0.0005 for PyVAN);
and higher exposure to MMF at M3 (AUC > 50 h.mg/L, p=0.006 for high-level viruria,
p=0.02 for viremia and p=0.01 for PyVAN). In multivariate analysis, DGF (RR=2.31,
p=0.005), acute rejection in the first three months (RR=3.5, p=0.008), tacrolimus trough
levels > 10ng/mL (RR=4.24, p=0.05) and MPA AUC0-12h at M3 > 50 h.mg/L (RR=3.17;
p=0.04) remained risk factors for BK viremia and/or PyVAN. By ROC curve analysis, we
showed that MPA AUC0-12h at M3 > 50 h.mg/L predicted PyVAN with a sensitivity of 50%
and a specificity of 83%.
In this study, well known risk factors associated with BKV replication were confirmed.
Moreover, we described an association between high MMF exposure and high tacrolimus
trough levels at month 3 and BKV infection. These findings need to be confirmed in further
studies.
Key-words: BK virus nephropathy, kidney transplantation, mycophenolate mofetil, risk
factors, tacrolimus, drug therapeutic monitoring