Mycophenolate Mofetil Does Not Modify the Incidence of Cytomegalovirus (CMV) Disease after Kidney Transplantation but Prevents CMV-Induced Chronic Graft Dysfunction
MAGALI GIRAL*,
JEAN MICHEL NGUYEN,
PASCAL DAGUIN*,
MARYVONNE HOURMANT*,
DIEGO CANTAROVICH*,
JACQUES DANTAL*,
GILLES BLANCHO*,
REGIS JOSIEN*,
DARIA ANCELET* and
JEAN PAUL SOULILLOU*
*Institut de Transplantation et de Recherche en Transplantation (ITERT) and
INSERM U437, Nantes, France. Service de Biostatistique, PIMEST, Nantes University Hospital, Nantes,
France.
Correspondence to Dr. Jean Paul Soulillou, ITERT, 30, INSERM U437, 30
Boulevard Jean Monnet, 44093 Nantes Cedex 1, France. Phone: 33-2-40-08-74-10;
Fax: 33-2-40-08-74-11; E-mail:
jps{at}nantes.inserm.fr
Abstract. Ganciclovir, which is used to treat cytomegalovirus
(CMV)infection, has been shown in rodent models to abolish CMV-mediated
chroniccellular damage and endothelial cell proliferation; when associated
withmycophenolate mofetil (MMF), it has been shown to increase its
anti—herpesvirus activity. This study tested the hypothesis that kidney
graftrecipients who received antirejection prophylaxis with MMF andwho were
treated with ganciclovir for a declared CMV diseasecould be protected from
chronic graft dysfunction. Investigatedwas the impact of ganciclovir-treated
CMV diseases in consecutivefirst kidney recipients according to their
immunosuppressivetherapy. The azathioprine (Aza)-treated group (Aza group)
included319 patients. The MMF-treated group (MMF group) included 126
patients.CMV disease was clinically defined and confirmed by virological
proofof CMV infection and was treated for at least 14 d with ganciclovir.
Despitehaving the same incidence (21.6% in the Aza group versus
24.6%in the MMF group) and severity, CMV disease was significantlyassociated
with graft loss independent of acute rejection episodesor other factors when
tested in a Cox proportional model inthe Aza group only (P <
10-4). It was shown for the firsttime that patients whose CMV
disease is treated with ganciclovirwhile they are on MMF therapy are
protected from the long-termdeleterious consequences of CMV disease on graft
survival, independentof acute rejection. It is suggested that the enhanced
anti—herpesvirus activity of ganciclovir by MMF could contribute to
thisreported effect, which may represent a significant contributionof MMF
efficacy to graft survival.
Kidney graft survival has increased progressively during thepast decade.
Several parameters, which have not yet been identifiedclearly, play a role in
the improvement of graft prognosis.These include the use of new
immunosuppressive therapies; thereduced incidence of acute rejection (AR)
episodes; and betterdetection, prevention, and management of opportunistic
infections,in particular cytomegalovirus (CMV) disease
(1,2).
CMV infectionhas been recognized as a major risk factor for human heart
(3)and kidney graft loss
experimentally (4) as well as
in humans,in association (5)
or not with AR (6). Moreover,
it has beenshown that CMV itself increased the incidence of AR in human
kidneygraft (7). New
immunosuppressive drugs, such as mycophenolatemofetil (MMF), which recently
have become more widely used ingraft recipients, have been suggested to
increase further theincidence of CMV disease when compared with Aza
(8). For avoidingthe
deleterious consequences of CMV infection on morbidity andgraft survival, new
prophylaxis strategies using orally administeredantiviral drugs, such as
ganciclovir (9) or, more
recent, valacyclovir(because of good sensitivity of CMV to this drug and its
betterbioavailability)
(10,11),
are now being applied. In recent studies,Neyts et al.
(12,13)
made the significant observation that MMFenhances the anti—herpes virus
activity of ganciclovirand acyclovir both in vitro and in
vivo in rodents. Since 1996,all kidney graft recipients in our center
have systematicallyreceived MMF instead of Aza within their immunosuppressive
treatmentand no antiviral prophylaxis, irrespective of the viral statusof
both donor and recipient before surgery. However, all patientswith CMV
infection and clinical or biologic symptoms underwenta 14-d course with
ganciclovir.
In this study, we revisited the impact on long-term graft survivalof overt
CMV infections treated with ganciclovir in a cohortof 126 first consecutive
kidney graft recipients who all receivedan antirejection prophylaxis with MMF
compared with 319 consecutiveprimary transplant recipients who received Aza.
Our data showthat CMV diseases have the same incidence whether patients are
onMMF or Aza therapy but that treatment of CMV episodes with ganciclovirwhen
patients are on MMF therapy abrogates CMV-related long-termkidney graft
alteration. This could have several potentiallyimportant implications
concerning the understanding of the mechanismsinvolved in chronic rejection
and the management of CMV infectionin human allografts.
Patients
A population of 445 adult patients who received a first kidneygraft at our
center from January 1990 to July 1999 were includedin this study. During this
period, no patient received a prophylacticor preemptive treatment to prevent
CMV infection. All patientshad a follow up of at least 1 yr. All clinical and
biologicdata concerning the patients were computerized and validated
independentlyfrom the medical team by a specialized clinical research
assistant.
Treatment
Patients were classified according to their immunosuppressivetherapy on
the day of transplantation. Two groups were defined.The first group, the
Aza-treated group (Aza group), included319 consecutive patients from 1990 to
1995. All were treatedwith a sequential therapy consisting of Aza (Imurel;
Glaxo-Welcome,Paris, France) at 2 mg/kg per d, corticosteroids (Cortancyl;
Roussel,Puteaux, France) at a starting dose of 1 mg/kg per d, and a
polyclonalantithymocyte globulin (ATG; Thymoglobuline; IMTIX Sangstat,Lyon,
France) as induction therapy. ATG was given at 1.5 mg/kgper d followed by
cyclosporin (CsA) (Sandimmune; Novartis, ReuilMalmaison, France) at a
starting dose of 8 mg/kg per d. Thesecond group, the MMF-treated group (MMF
group) included 126consecutive patients from 1996 to July 1999. In this
group,83 recipients received MMF at 2 g/d (Cellcept; Roche, Neuilly-sur
Seine,France), Neoral (Novartis) at a starting dose of 8 mg/kg perd from the
first day of transplantation, and steroids at 1 mg/kgper d. The other 43
patients who were considered to be at riskof delayed graft function
(14) according to their
historicalanti-human leukocyte antigen (HLA) immunization (25% of T cells
panel)or to a prolonged ischemia time (36 h) received MMF (2 g/d),
steroids(1 mg/kg per d), and a 10-d course of ATG (1.5 mg/kg per d)followed
by delayed Neoral (8 mg/kg per d; sequential induction).In both the Aza and
the MMF groups, the corticosteroid regimenwas decreased by 10 mg every 5 d to
a dose of 10 mg/d and inmost cases stopped before 3 mo of follow-up, as
described previously(15). The
dose of ATG was monitored via the E-rosette test
(16).The CsA dosage was
adjusted to yield blood levels between 150and 250 ng/ml, as measured by a
monoclonal radioimmunoassay.Long-term Aza and MMF doses were adjusted
according to whiteblood cell counts (WBC).
Definition of AR
AR was diagnosed on the grounds of clinical symptoms and wasconfirmed by
kidney biopsy examination in all cases, exceptwhen technically impossible. In
this event, rejection episodeswith intention-to-treat and response to the
treatment were takeninto account. AR treatment consisted of intravenous
corticosteroid(Solumedrol; Upjohn, Paris, France) boluses for 5 consecutive
days,followed by ATG in the event of steroid resistance (stable orincreased
blood creatinine after the last bolus and absenceof histologic
improvement).
Definition of CMV Disease
CMV disease was defined as the association of fever with oneor more of the
following clinical or biologic signs: leukopenia,gastrointestinal disease,
pancreatitis, hepatitis, pneumonitis,nephritis, or myalgia/arthralgia (see
Table 1). Virologic proofof
CMV infection was obtained for all patients by rapid viremia
(±viruria),seroconversion, qualitative DNA PCR testing, or histologic
evidenceof endothelial cell inclusion by viral particles. Serious CMVdisease
was defined according to the involvement of solid organs.Each episode,
confirmed virologically, was treated for at least14 d with ganciclovir. Aza
and MMF were decreased similarlyaccording to WBC in the acute phase.
Table 1. Repartition of biological and clinical
manifestationa
Statistical Analyses
To compare the demographic characteristics of the Aza and theMMF groups,
we tested all variables with the t test or the 2
test.The Kaplan-Meier estimate and log rank test were used to comparethe
profile of graft failure after transplantation. Patientswho died during the
study were considered as transplant failure.To assess the combined effect of
historical factors and theCMV disease on graft survival as possible
independent risk factors,we used a Cox's proportional hazards multiple
regression analysison the patients of the Aza group who never underwent an AR
episode.The duration of delayed graft function (defined as the timeto reach
a creatinine Cockroft calculated clearance 10 ml/minafter surgery
(14)) was tested as a
time-dependent variableand included in the model with the other following
variables:recipient and donor age (55; >55), recipient and donor sex,
andHLA-A-B-DR incompatibilities (0-1; >1). The effect of CMVdiseases was
assessed using a 2 test of the log likelihood betweenthe
model stratified on the CMV disease and the model withoutCMV disease. A 5%
level of significant was used. Survival analyseswere performed with BMDP 7.0
(Statistical Software, Los Angeles,CA) and SPLUS 2000 (Mathsoft
International, Surrey, UK) softwarepackages.
Patient Characteristics
The 126 consecutive recipients within the MMF group (from 1996)had similar
characteristics, either they received (43 patients)or did not receive (83
patients) a course of induction therapywith ATG, excepted for cold ischemia
time (31.8 ± 10h [range, 16 to 49 h] versus 19.8 ±
10.6 h [range, 1.6to 41 h], respectively) and the historical level of anti T
panelreactive antibodies (13 ± 2.7% [range, 1 to 100%] versus
2.7± 9.5% [range, 0 to 69%], respectively), which were thecriteria to
add or not to add ATG to the MMF regimen. Therewas no other difference in
demographic characteristics betweenthe Aza group and the MMF group, as shown
in Table 2. Graftsurvival
within the MMF group did not differ between patientswho received ATG and
those who did not receive ATG in additionto MMF but was significantly better
than in the Aza group, inwhich all patients received an induction with ATG
(93 versus87%, respectively, at 1 yr; P < 0.01;
Figure 1).
Figure 1. Kaplan-Meier analysis of graft survival according to immunosuppressive
regimens: solid line, mycophenolate mofetil (MMF)-treated group (MMF group;
MMF and steroids in association with cyclosporin [CsA] ± antithymocyte
globulin [ATG], i.e., sequential induction; n = 126); dashed
line, azathioprine (Aza)-treated group (Aza group; Aza and steroids in
association with CsA and ATG, i.e., sequential induction; n
= 319). The difference is significant (P < 0.01). The MMF group
corresponds to a consecutive cohort of patients who received a transplant
after 1996; the Aza group corresponds to a cohort of consecutive patients who
received a transplant before 1996.
CMV Disease
The incidence of CMV disease was similar in both groups: 21.6%in the Aza
group versus 24.6% in the MMF group (having receivedor not received
ATG for induction therapy, 24 versus 25%, respectively).CMV disease
occurred and was treated at a similar time in bothgroups: 50 ± 43 d
(range, 22 to 335 d) in the MMF groupversus 56 ± 30 d (range,
20 to 185 d) in the Aza group(not significant). All patients were treated
with ganciclovirfor at least 14 d at a dose adapted to renal function. No
differencesin the severity of the CMV disease were observed between thetwo
groups according to the involvement of solid organs
(Table 1).
Impact of CMV Disease on Graft Survival According to
Immunosuppressive Therapy
The impact of CMV disease on graft survival in the Aza and theMMF groups
was analyzed. CMV disease was found to be associatedstrongly with graft loss
only in the Aza group (Figure
2). However,surprising was that despite the same incidence,
severity, anduse of antiviral treatment of the CMV disease as in the Aza
group,the negative impact on long-term graft survival in the morerecent
patients in the MMF group was totally lost
(Figure 3).Furthermore, graft
survival was increased significantly at 1yr in patients in the MMF group
compared with those in the Azagroup (77 versus 90%; P <
0.02) but only in patients whodeveloped CMV disease during their follow-up
(Figure 4). Itis interesting
that there also was no difference in graft survivalbetween patients of the
Aza group and the MMF group withoutCMV disease
(Figure 5). This indicates that
the graft prognosiswas almost the same in patients who never contracted a CMV
diseaseregardless of their immunosuppressive regimen and thereforethat most
of the MMF effect could have an impact on patientswith CMV. In summary, our
data show that under MMF therapy,the CMV diseases that were treated with
ganciclovir lost theirassociation with long-term functional alterations of
the graft.
Figure 2. Kaplan-Meier analysis of graft survival according to cytomegalovirus (CMV)
disease treated with ganciclovir (dashed line; n = 69) or no CMV
(solid line; n = 234) in the Aza group. CMV disease seems to be as a
strong prognostic factor for graft loss (P < 0.01).
Figure 3. Kaplan-Meier analysis of graft survival according to CMV disease treated
with ganciclovir (solid line; n = 31) or no CMV (dashed line;
n = 91) in the MMF group. CMV disease while the patients are treated
with ganciclovir does not modify the long-term graft outcome of patients who
are on MMF therapy.
Figure 4. Kaplan-Meier analysis of graft survival in patients who developed CMV
disease that was treated with ganciclovir. Solid line, patients who were
treated with MMF (n = 31); dashed line, patients who were treated
with Aza (n = 69).
Figure 5. Kaplan-Meier analysis of graft survival in patients who did not have CMV
disease and who were treated with ganciclovir while on MMF therapy (solid
line; n = 91) or Aza therapy (dashed line; n = 234).
Patients who never developed CMV disease had a similar graft survival,
regardless of their immunosuppressive regimen.
Relationship between AR and CMV Disease According to
Immunosuppressive Therapy
The incidence of AR was significantly lower (P < 0.01) inthe
MMF group than in the Aza group with 14 versus 27% of patients
presentingone or more AR. However, the number of patients who presentedboth
a CMV disease and an AR episode was almost the same inthe two groups (8
versus 5%, respectively). Therefore, the differencein graft survival
between the Aza and MMF groups could not beexplained by a difference in CMV
disease frequency in patientswith AR. Moreover, graft survival in patients of
the Aza groupwho never underwent AR was significantly lower (P <
0.05)when there was a history of CMV disease during the follow-up,indicating
that CMV disease was, by itself, a prognostic factorfor long-term graft
survival (Figure 6). However,
because ofan interaction between different variables and CMV disease,a Cox's
model with stratification was used. The model adjustedwith the historical
variables (recipient and donor age and gender,HLA incompatibilities, delayed
graft function) had a log likelihoodequal to -301.02, whereas the model
adjusted with the historicalvariables and stratified on the CMV disease had a
log likelihoodequal to -265.77, showing clearly that the CMV disease was a
significantand independent risk factor of graft loss in the patient inthe
Aza group who never underwent an AR episode (P < 0.0001;
Table 3).Finally, in patients
without CMV disease, despite an incidenceof AR higher but not statistically
significant in the Aza groupthan in the MMF group (24.5 versus 15%;
P < 0.1; Figure 5),
graftsurvival was similar in both groups, confirming that CMV diseasewas,
independent of AR episodes, a strong prognostic factorfor graft loss in the
Aza group.
Figure 6. Kaplan-Meier analysis of graft survival in patients who were on Aza therapy
and who never experienced an acute rejection (AR) episode, according to the
presence (dashed line; n = 40) or absence (solid line; n =
178) of CMV disease that was treated with ganciclovir. CMV infection by itself
(i.e., independent from AR) is a significant risk factor for graft
loss while patients are on Aza therapy.
MMF was introduced recently to the immunosuppressive regimenof graft
recipients, replacing Aza. MMF administration duringthe first 6 mo after
transplantation was demonstrated in a randomizedblind study to decrease
significantly (to 19.7%) the incidenceof AR episodes in recipients of first
kidney grafts (17). More
recent,it also was suggested that MMF-based maintenance regimens couldhave a
further impact on long-term graft survival in recipientsof kidney allografts
(18), suggesting that this
drug may influencethe chronic rejection process.
In this article, we provide data indicating that kidney recipientswho
received MMF (MMF group) in addition to CsA and corticosteroidsfor
antirejection prophylaxis, in association or not with aninduction prophylaxis
with ATG, have an incidence of CMV diseasesimilar to those systematically
treated with ATG followed byCsA and in addition to Aza and corticosteroids
(Aza group).We already showed in a randomized comparison of triple therapy
versusATG induction after simultaneous pancreas-kidney
transplantation(19) that ATG
was associated with a higher incidence of CMVdisease. However, in this study,
we did not observe increasedincidence of CMV disease in patients who had
received ATG/MMF(n = 43) and those who did not receive ATG
(n = 83) (24 versus25%, respectively). We also confirm that
CMV disease is a riskfactor for graft loss in patients who are treated with
Aza,independent of AR. Moreover, our data show for the first timethat kidney
graft survival in the group of patients who receivedMMF and developed CMV
disease was not different from that inpatients who did not have CMV disease.
The magnitude of theindependent impact of CMV disease on graft survival is
illustratedfurther by the fact that graft survival in patients in the two
groups(Aza or MMF) who never developed CMV disease was not different,despite
the dramatically higher number of AR episodes in patientsin the Aza group
than those in the MMF group. Furthermore, asMMF/Neoral maintenance therapy
likely exposed patients in theMMF group to a more profound immunosuppression
than in the Aza/Sandimmunegroup, CMV diseases would have been expected to be
more deleteriousin the MMF group, which was not the case
(20), suggesting furthera
specific effect of MMF on the virus itself.
It is now well established that CMV infection by itself increaseschronic
cellular allograft damage, vascular and endothelialintracellular adhesion
molecule-1 expression in the rat kidney
(21,22),
allograftendotheliitis (23),
and endothelial cell proliferation as wellas intimal thickening in rat
cardiac allografts
(24,25).
Lemströmet al.
(26) demonstrated that
ganciclovir prophylaxis in therat abolished the CMV-mediated cardiac
vasculopathy in a dose-dependentmanner. It is interesting that Neyts et
al.
(12,13)
recentlyobserved that MMF could strongly potentiate (up to 350-fold)the
anti—herpes virus (HSV-1, HSV-2, human CMV, and varicellazoster)
activity of acyclovir and ganciclovir, both in vitroand in
vivo, in a murine model. It is our belief that this importantproperty
could explain the mechanisms underlying the findingthat no late graft loss
occurred in the cohort of patients withCMV disease treated by ganciclovir
when on MMF therapy. We hypothesizethat patients who were treated with MMF
for antirejection prophylaxisand who developed a CMV disease that was treated
with ganciclovir,may have been protected from the deleterious effects of CMV
ontheir allografts and their consequences, including graft dysfunction,as a
result of a better antiviral efficacy of ganciclovir. Additionalexperiments
are scheduled to investigate whether MMF/ganciclovirtreatment results in a
total viral clearance of the injuredgrafts.
Our findings also suggest that the protective effect of MMFon CMV-mediated
injury may account for most of its overall beneficialinfluence on kidney
graft survival and may contribute to understandingwhy the impact of MMF on
long-term survival has been relatedmostly to its administration during the
first year after transplantation
(27),a period when CMV
disease generally occurs. However, other featuresof MMF could explain or
contribute to decreased chronic rejection
(28),such as a possible
effect in the control of smooth muscle cellproliferation
(29), in addition to its
immunosuppressive effects
(30).
In summary, we showed that the incidence of the CMV diseaseand its
resulting morbidity when treated with ganciclovir wassimilar in patients who
were on MMF or Aza antirejection therapy.However, we showed for the first
time that patients who areon MMF therapy and who experienced a CMV disease
that was treatedwith ganciclovir were protected from the long-term graft loss
observedin a historical cohort of patients with CMV disease that wastreated
by ganciclovir while the patient was on Aza therapy.
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Received for publication May 18, 2000.
Accepted for publication January 26, 2001.
This article has been cited by other articles:
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S3 - S9.
[Abstract][Full Text][PDF]
J. Dantal and J.-P. Soulillou Immunosuppressive Drugs and the Risk of Cancer after Organ Transplantation
N. Engl. J. Med.,
March 31, 2005;
352(13):
1371 - 1373.
[Full Text][PDF]
K. C. Abbott, S. J. Swanson, L. Y.C. Agodoa, and P. L. Kimmel Human Immunodeficiency Virus Infection and Kidney Transplantation in the Era of Highly Active Antiretroviral Therapy and Modern Immunosuppression
J. Am. Soc. Nephrol.,
June 1, 2004;
15(6):
1633 - 1639.
[Abstract][Full Text][PDF]
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Abstract
Introduction
25% of T cells
panel) or to a prolonged ischemia time (
2
test. The Kaplan-Meier estimate and log rank test were used to compare the
profile of graft failure after transplantation. Patients who died during the
study were considered as transplant failure. To assess the combined effect of
historical factors and the CMV disease on graft survival as possible
independent risk factors, we used a Cox's proportional hazards multiple
regression analysis on the patients of the Aza group who never underwent an AR
episode. The duration of delayed graft function (defined as the time to reach
a creatinine Cockroft calculated clearance 
55; >55), recipient and donor sex,
and HLA-A-B-DR incompatibilities (0-1; >1). The effect of CMV diseases was
assessed using a 
