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Ever
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dinal study charted the course of CAN in 120 renalinhibitors), sirolimus (Rapamune, Wyeth Pharmaceuticals,
Madison, NJ), and everolimus (Certican, Novartis Pharma
AG, Basel, Switzerland) has potential in this respect. This
Transplantation Reviewsdyslipidemia, impaired wound healing, and proteinuria. A low incidence of malignancy has been observed with everolimus, and studies are
ongoing to examine its antitumor effects in the treatment of certain malignancies. It seems likely that everolimus will continue to play a role
in the development of reduced-exposure calcineurin inhibitor regimens and has considerable potential to improve outcomes for transplant
recipients, focused perhaps on bold-for-oldQ transplant recipients and patients at high risk of poor graft function or malignancy. This reviewconsiders the available data on the clinical application of everolimus and identifies current and future strategies for improving outcomes after
renal transplantation.
D 2006 Elsevier Inc. All rights reserved.
1. Introduction
Survival of renal organ transplant recipients has
improved greatly over the years, particularly since the
introduction of calcineurin inhibitors (CNIs), such as
cyclosporine (CsA), and purine biosynthesis inhibitors
(eg, mycophenolic acids [MPAs]). Renal graft survival
rates are now in the order of 90% at 1-year posttransplant
[1], but ensuring very long-term graft survival (ie, up to
10 years) remains a challenge. Chronic allograft nephrop-
athy (CAN), characterized by interstitial fibrosis and
tubular atrophy [2], is the main cause of renal graft loss,
although patient death is also an important cause of loss of
otherwise functioning grafts. Risk factors for the develop-
ment of CAN include acute rejection, use of CNIs,
cytomegalovirus (CMV) infection, and comorbidities such
as hypertension and hyperlipidemia [3]. A recent longitu-
transplant recipients [4]. Chronic allograft nephropathy
was shown to be a progressive, time-dependent process,
with much tubulointerstitial damage occurring within 1 to
2 years of transplantation. Later damage was characterized
by progressive arteriolar hyalinosis, ischemic glomerulo-
sclerosis, and further interstitial fibrosis associated with
CNI toxicity [4], highlighting the difficult balance that
physicians must achieve with CNIs, the mainstay of
immunosuppressive therapy. Despite their efficacy, these
agents were almost universally associated with nephrotoxic
effects at 10-year follow-up. Further improvements in renal
graft survival will depend on the development of immu-
nosuppressive regimens that can prevent CAN and do so
without inducing nephrotoxic effects. A new class of
immunosuppressant agents, proliferation signal inhibitors
(PSIs; also known as mammalian target of rapamycinEverolimus (Certican) in renal tran
data, current usage,
Julio Pascuala,4, Ioannis N.aServicio de Nefrologia, Hospital
bDepartment of Nephrology and TransplacServei de Nefrologia i Trasplantament Renal, Hospital Clnic
Abstract
The efficacy and tolerability of everolimus have been demonstra
clinical experience. The efficacy of everolimus after renal transpla
combining everolimus with full- or reduced-dose cyclosporine (CsA
the risk of acute rejection, particularly when combined with thera
elimination of calcineurin inhibitors is currently being investigated.
enhance CsA-related nephrotoxicity. Adverse events seen in trials o0955-470X/$ see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.trre.2005.10.005
E-mail address: jpascual.hrc@salud.madrid.org (J. Pascual).lantation: a review of clinical trial
d future directions
letisb, Josep M. Campistolc
n y Cajal, 28034 Madrid, Spain
n, Laiko Hospital, 15562 Athens, Greece
arcelona, Universitat de Barcelona, 08036 Barcelona, Spain
a number of clinical trials, and there is also an increasing body of
n is at least equivalent to that of mycophenolate mofetil. Studies
ve shown that CsA exposure can be minimized, without increasing
ic drug monitoring. A role for everolimus in regimens involving
olimus with significantly reduced-dose CsA has not been shown to
rolimus are generally class-specific and include edema, arthralgia,
20 (2006) 118
www.elsevier.com/locate/trrereview will concentrate on the clinical trial data for4 Corresponding author. Tel.: +34 913368018.
everolimus and its use in clinical practice.
2. Everolimusclinical development and efficacy in de
novo renal transplantation
2.1. Mechanism of action
Everolimus has a mode of action that is distinct from
CNIs, which inhibit the transcription of early T-cellspecific
genes, thus reducing the production of T-cell growth factors
such as interleukin (IL) 2 [5]. Everolimus acts at a later
stage of the cell cycle, blocking the proliferation signal
provided by these growth factors and preventing cells from
entering the S phase [5]. The antiproliferative actions of
everolimus are not limited to the immune system; it also
inhibits growth factordriven cell proliferation in general
(eg, reducing vascular smooth muscle cell proliferation) [5].
The antiproliferative effects of everolimus also prevent
vascular remodeling [6], a key component of progressive
(44% and 50%, respectively), with the most frequent
adverse events being headache in the everolimus groups
and dizziness among those receiving placebo. Mean
changes in laboratory parameters did not differ significantly
between everolimus and placebo groups. Importantly,
administration of everolimus in single doses did not appear
to affect the steady-state pharmacokinetics of CsA in these
individuals [14]. A further study in healthy individuals
evaluated coadministration of everolimus with 2 different
CsA formulationsa microemulsion (Neoral, Novartis
Pharma AG) and an oral solution (Sandimmune, Novartis
Pharma AG) [15]. Both CsA formulations were observed to
increase systemic exposure (area under the concentration-
time curve [AUC]) to everolimus, but the percentage or
increase was significantly greater for the microemulsion
formulation (P = .008). A 2- to 3-fold decrease in
raft dy
ermis
J. Pascual et al. / Transplantation Reviews 20 (2006) 1182allograft dysfunction (Fig. 1) [7].
Preclinical studies have demonstrated the immunosup-
pressive actions of everolimus in animal models of renal
transplantation [8-11]. Moreover, such models provide
evidence for synergistic activity between everolimus and
CsA, with the 2 combined agents offering more potent
immunosuppression than either one alone [8,12]. Animal
models have also been used to demonstrate the anti-
proliferative effect of everolimus on nonimmune cells.
For example, everolimus was associated with delayed
progression of CAN in a rat model of renal transplan-
tation because of antiproliferative or apoptosis-enhancing
effects [13].
2.2. Early clinical development
In the first study of everolimus in humans, 54 stable renal
transplant recipients split into 6 groups received either a
single dose of everolimus, ranging from 0.25 to 25 mg or
placebo in addition to CsA [14]. The safety of each dose
was monitored for 11 days before the next group of
individuals received a higher dose. All doses of everolimus
were well tolerated. Similar proportions of patients receiv-
ing everolimus and placebo had at least 1 adverse event
Fig. 1. Vascular remodeling in transplanted organs, a key component of allog
to cytokine release and up-regulation of growth factors. Reproduced with peverolimus exposure can therefore be expected after
withdrawal of CsA from immunosuppressant regimens.
This pharmacokinetic interaction may be due to direct
competition between everolimus and CsA because both
agents undergo metabolism by CYP3A4 and are substrates
of P-glycoprotein. Conversely, if CsA is added to an
everolimus-containing regimen, an average 3-fold increase
in systemic exposure to everolimus is observed [16].
After administration of single doses of everolimus
(0.2515 mg) to 7 renal transplant recipients also receiving
standard CsA immunosuppression, the pharmacokinetics of
CsA were again unaffected by everolimus administration
[17]. The mean maximal plasma concentration (Cmax) of
everolimus (dose normalized to 1 mg everolimus) was 7.9F2.7 lg/L, whereas the mean time to maximum plasmaconcentration (Tmax) was 1.5F 0.9 hours. In a larger phase Istudy, 24 renal transplant recipients were given everolimus
0.75, 2.5, or 7.5 mg/d, or placebo for 4 weeks [18]. Mean
initial Tmax varied from 1.3 F 0.3 to 1.8 F 0.5 hours forthe 3 everolimus groups, and steady state was reached
within 4 days. The mean elimination half-life was 19.2 F3.4, 18.1 F 7.6, and 16.0 F 5.6 hours for the 0.75, 2.5,and 7.5-mg groups, respectively. The pharmacokinetics of
sfunction. Continued immune and endothelial activation posttransplant lead
sion from Neumayer [7].
everolimus showed dose-exposure proportionality and a
good correlation between trough and AUC concentrations.
The most frequently occurring adverse event was an
increased incidence of infection. Thrombocytopenia and
hyperlipidemia occurred in a dose-dependent manner.
In a phase II trial, 101 de novo renal transplant
recipients receiving everolimus 1.0, 2.0, or 4.0 mg/d were
monitored for 1 year posttransplant [19]. Steady-state
pharmacokinetics was achieved on or before day 7. Cmaxand systemic exposure (AUC) were proportional to ever-
olimus dose, with AUC being stable throughout follow-up.
Pharmacokinetic parameters associated with CsA treatment
did not differ with administration of everolimus at any
dose. The incidence of acute rejection was analyzed in 103
de novo renal transplant recipients who were randomized
to receive everolimus 1.0, 2.0, or 4.0 mg/d in addition to
CsA and corticosteroids [20]. Over the first 6 months of
treatment, 32.4%, 14.7%, and 25.7% of patients in the
respective treatment groups experienced biopsy-proven
acute rejection (BPAR). Compared with the everolimus
1.0 mg/d group, the incidence of moderate and severe
BPAR was significantly lower in the 2.0 and 4.0 mg/d
groups (P = .002 and .006, respectively). Everolimus was
generally well tolerated, although viral and fungal infec-
tions were more common in patients receiving the highest
dose. As in previous studies, blood lipid levels were
elevated during everolimus treatment, requiring lipid-
2.3. Clinical efficacy studies
Clinical development of everolimus in de novo renal
transplantation was supported by a long-term phase II study
and 4 major phase III clinical trials (Table 1). A 3-year
phase II trial (study B156) compared the efficacy and
tolerability of everolimus in combination with full- and
reduced-dose CsA [21]. Two 3-year phase III trials (studies
B201 and B251) were conducted to establish whether
everolimus was similar in efficacy to mycophenolate mofetil
(MMF) in renal transplantation when both agents were
combined with full-dose CsA and corticosteroids [22-24].
Subsequently, the efficacy of everolimus in combination
with reduced-dose CsA was investigated with the aim of
establishing immunosuppressive regimens with lower CNI-
induced nephrotoxicity (studies A2306 and A2307) [25].
2.3.1. Everolimus vs MMF with full-dose CsA
The large-scale trials, studies B201 [22,23] and B251
[24], were of a similar design, with de novo renal transplant
recipients being randomized to receive fixed doses of
everolimus 1.5 mg/d, everolimus 3.0 mg/d, or MMF
2.0 g/d in a blinded fashion for 1 year, followed by 2 years
of open-label treatment. In addition, all patients received
full-dose CsA microemulsion (Neoral) and corticosteroids.
The primary objective in both cases was to compare the
incidence of an efficacy composite end pointefficacy
le)
le)
re CsA
J. Pascual et al. / Transplantation Reviews 20 (2006) 118 3lowering agents.
Table 1
Clinical trials for the development of everolimus in renal transplantation
Study Study design Study duration
B156 Phase IIrandomized,
open-label, parallel-group
3 y
B201 Fixed-dose everolimus 3 y
Phase IIIrandomized,
double-blind, double-dummy,
parallel-group
Open study years 23
B251 Fixed-dose everolimus 3 y
Phase IIIrandomized,
double-blind,
double-dummy,
parallel-group
Open study years 23
A2306 Concentration-controlled
everolimus
1 y (6-mo data availab
Phase IIIrandomized,
open-label, parallel-group
A2307 Concentration-controlled
everolimus
1 y (6-mo data availab
Phase IIIrandomized,
open-label, parallel-group
a In combination with basiliximab and corticosteroids.b In combination with standard-dose CsA and corticosteroids.c In combination with standard-dose CsA and prednisone.d In combination with corticosteroids and reduced-exposure CsA.e In combination with basiliximab, corticosteroids, and reduced-exposufailurein each treatment group at 12 or 36 months
Treatment Patients (n) References
Everolimus 3.0 mg/d +
full-dose CsAa53 Nashan et al [21]
Everolimus 3.0 mg/d +
reduced-dose CsAa58
Everolimus 1.5 mg/db 194 Vtko et al [22,23]
Everolimus 3.0 mg/db
MMF 2.0 g/db198
196
Everolimus 1.5 mg/dc 193 Lorber et al [24]
Everolimus 3.0 mg/dc
MMF 2.0 g/dc194
196
Everolimus 1.5 mg/dd
Everolimus 3.0 mg/dd112
125
Vtko et al [25]
Everolimus 1.5 mg/de
Everolimus 3.0 mg/de117
139
Vtko et al [25]
.
posttransplant. Efficacy failure was defined as the incidence
of BPAR, graft loss, death, or loss to follow-up. Secondary
end points included allograft and patient survival, as well as
the incidence of acute rejection and safety parameters.
The incidences of efficacy failure, BPAR, graft loss, and
death at 12 and 36 months of follow-up in studies B201 and
B251 are shown in Fig. 2 and were similar among patients
randomized to MMF and everolimus 1.5 or 3.0 mg/d.
Furthermore, the therapeutic equivalence of everolimus and
MMF was maintained in the long term, as there were no
significant differences between efficacy end points in either
trial at 36 months of follow-up [23,24]. A significant
difference between the treatment arms was noted in study
B251 [24], in which the incidence of antibody-treated acute
rejection was significantly lower among patients receiving
everolimus 1.5 mg/d than among those receiving MMF at
12 months (7.8% vs 16.3%; P = .01) and 36 months of
follow-up (9.8% vs 18.4%, respectively; P = .014). In both
studies, most graft loss occurred within the first 12 months
of treatment. In study B251, reasons for graft loss included
infection, acute and chronic rejection, kidney infarction, and
recurrence of original disease [24].
The interactions noted in studies B201 and B251
highlighted that therapeutic drug monitoring (TDM) could
be beneficial for patients receiving everolimus and CsA.
Analysis of data from 779 patients in the 2 trials showed that
everolimus trough blood levels of 3 ng/mL or more were
necessary to gain most clinical benefit from the agent [26].
Risk of BPAR was 3.4-fold higher for patients with
everolimus trough blood levels less than 3 ng/mL compared
B201
J. Pascual et al. / Transplantation Reviews 20 (2006) 1184Fig. 2. Efficacy analyses at 12 and 36 months of follow-up in clinical trials
graft loss, death, loss to follow-up [22-24].and B251 (intent-to-treat population). Primary efficacy is defined as BPAR,
J. Pascual et al. / Transplantation Reviews 20 (2006) 118 5with patients whose trough blood levels were in the range 3
to 8 ng/mL (P b .0001) (Fig. 3) [26]. There was a trendtoward even lower rates of BPAR in patients with ever-
olimus trough blood levels greater than 8 ng/mL, but this
finding should be interpreted cautiously given the small
number of patients in this group. It was estimated that after
initiation of everolimus at a dose of 1.5 mg/d, 2 TDM-led
dose adjustments would be sufficient for 84% of patients to
achieve everolimus trough blood levels in excess of
3 ng/mL. With respect to renal function, the TDM analysis
showed that risk of serum creatinine levels of 200 lmol/L ormore increased greatly with increasing CsA trough levels,
but was affected only slightly by everolimus trough blood
levels [26].
Monitoring of serum creatinine levels in studies B201
and B251 showed that patients receiving everolimus
Fig. 3. Kaplan-Meier plots over the first 6 months of treatment showing the
percentage of patients free from BPAR at different everolimus trough blood
levels (n = 779). Reproduced with permission from Lorber et al [26].exhibited higher mean serum creatinine levels than those
receiving MMF [22-24]. At 12 months of follow-up, a
protocol amendment was introduced in both trials allowing
for lower CsA trough blood levels (5075 ng/mL) to be
targeted in the everolimus groups, provided everolimus
trough blood levels were at least 3 ng/mL. Mean serum
creatinine levels subsequently decreased slightly or
remained stable in everolimus-treated patients, and CsA
reduction was not accompanied by an increase in BPAR.
Everolimus itself does not induce renal dysfunction, but
these findings appeared to indicate that it can potentiate
CsA-related nephrotoxicity. A similar effect has been noted
in patients receiving sirolimus [27].
In addition to efficacy and safety analyses, an economic
evaluation of treatment was also carried out during study
B201 [28]. At 12 months of follow-up, mean overall
treatment costs were US$33 715, US$38 519, and US$36
509 for the everolimus 1.5 mg, everolimus 3.0 mg, and
MMF groups, respectively. Differences in cost between the
treatment groups were not significant.2.3.2. Everolimus combined with full- or reduced-dose CsA
After protocol amendment, data from studies B201 and
B251 indicated that everolimus plus reduced-exposure CsA
could result in improved renal function without increased
risk of rejection. This is supported by the findings of a
3-year phase II trial (study 156) in which patients received
everolimus 3.0 mg/d in combination with basiliximab,
corticosteroids, and either full- (n = 53) or reduced-dose
(n = 58) CsA microemulsion [21]. From 3 to 36 months of
follow-up, target CsA trough blood levels were 125 to
250 ng/mL in the full-dose CsA group, compared with 50
to 100 ng/mL in the reduced-dose CsA group. The
incidence of efficacy failure (BPAR, graft loss, death, or
loss to follow-up) was significantly lower in the reduced-
dose CsA group compared with the full-dose CsA group at
6 (P = .046), 12 (P = .012), and 36 (P = .032) months
of follow-up [21]. More specifically, BPAR was less
frequent in the reduced-dose CsA group than in the full-
dose CsA group at each follow-up time point: 6 months,
3.4% vs 15.1%; 12 months, 6.9% vs 17.0%; and
36 months, 12.1% vs 18.9%, respectively.
Importantly, at 6 and 12 months of follow-up, mean
serum creatinine levels were numerically lower in patients
randomized to reduced CsA dosing than in those receiving
full-dose CsA [21]. The advantage of reduced-dose CsAwas
more evident in relation to mean creatinine clearance values,
which were significantly higher in the reduced-dose group
at 6 (P = .009) and 12 (P = .007) months of follow-up.
Patients remaining on treatment at 12 months were treated
according to an amended protocol to optimize their renal
function: CsA dosing was adjusted to achieve trough blood
levels of 50 to 75 ng/mL, whereas everolimus dose was
adjusted to ensure trough blood levels of at least 3 ng/mL
(in accordance with TDM study findings). After transition to
the amended protocol, mean serum creatinine levels in the
full-dose CsA group fell. In patients randomized to reduced-
dose CsA, mean serum creatinine and creatinine clearance
values remained stable, reflecting the smaller reduction in
CsA dose for this group [21].
Overall, study B156 demonstrated how synergy between
everolimus and CsA permitted reduced-dose CsA, resulting
in lower rates of efficacy failure and improved renal
function compared with everolimus and full-dose CsA [21].
2.3.3. Concentration-controlled everolimus plus
reduced-exposure CsA
Therapeutic use of everolimus in combination with CsA
was further refined in 2 similarly designed phase III clinical
trials in which TDM was used to optimize everolimus
dosing, and the CsA blood levels 2 hours after administra-
tion (C2 monitoring) was used to guide reduction in CsA
exposure [25]. In study A2306, concentration-controlled
everolimus 1.5 or 3.0 mg/d was combined with reduced-
exposure CsA (given as CsA microemulsion) and cortico-
steroids; the same approach was used in study A2307
with the exception that patients also received doses of
and A2307) examining the use concentration-controlled everolimus with reduced-
out basiliximab) Study A2307 (with basiliximab)
/d Everolimus 3.0 mg/d Everolimus 1.5 mg/d Everolimus 3.0 mg/d
2) 62 (62) (n = 111) 66 (66) (n = 107) 67 (65) (n = 123)
2) 62 (65) (n = 125) 64 (68) (n = 117) 65 (65) (n = 139)
2) 61 (63) (n = 125) 63 (60) (n = 117) 61 (60) (n = 139)
5) 132 (140) (n = 112) 130 (137) (n = 113) 130 (136) (n = 127)
2) 126 (134) (n = 125) 128 (132) (n = 117) 126 (132) (n = 139)
2) 128 (141) (n = 125) 142 (136) (n = 117) 142 (136) (n = 139)
24/125 (19.2%) 18/117 (15.4%) 27/139 (19.4%)
32/125 (26%) 23/117 (20%) 34/139 (25%)
34/125 (27%) 23/117 (20%) 34/139 (25%)
19/125 (15.2%) 16/117 (13.7%) 21/139 (15.1%)
24/125 (19%) 16/117 (13.7%) 22/139 (15.8%)
26/125 (21%) 19/117 (16%) 25/139 (18%)
J. Pascual et al. / Transplantation Reviews 20 (2006) 1186basiliximab on the day of transplantation and 4 days later.
Everolimus dose was adjusted to ensure trough blood levels
of at least 3 ng/mL. In study A2306, CsA C2 level target
ranges were 1000 to 1400 ng/mL during weeks 0 to 4, 700
to 900 ng/mL during weeks 5 to 8, 550 to 650 ng/mL during
weeks 9 to 12, and 350 to 450 ng/mL thereafter. Because of
the use of induction therapy, target CsA C2 ranges were set
lower in study A2307: 500 to 700 ng/mL during weeks 0 to
8 and 350 to 450 ng/mL from week 9 onward.
The primary end point of the trials was renal function as
assessed by glomerular filtration rate (GFR) and creatinine
clearance or serum creatinine [25]. Table 2 shows values for
GFR and serum creatinine at 6, 12, and 24 months of
follow-up in both trials [25,29-33]. Serum creatinine values
were substantially lower than those observed among
patients receiving everolimus with full-dose CsA in study
Table 2
Renal function and efficacy parameters in 2 similarly designed trials (A2306
exposure CsA in renal transplantation [25,29-33]
Follow-up period (mo) Study A2306 (with
Everolimus 1.5 mg
Renal function
Median (mean)
calculated GFR
(creatinine clearance;
mL/min)
6 65 (63) (n = 10
12 69 (69) (n = 11
24 68 (66) (n = 11
Median (mean) serum
creatinine (lmol/L)6 133 (147) (n = 10
12 122 (126) (n = 11
24 129 (133) (n = 11
Efficacy
Efficacy failure, n (%) 6 31/112 (27.7%)
12 31/112 (28%)
24 34/112 (30%)
BPAR, n (%) 6 28/112 (25%)
12 29/112 (26%)
24 30/112 (27%)B251 [24].
Efficacy end points are also listed in Table 2. The
incidence of efficacy failure in both studies was equivalent
to, or lower than, that in earlier studies in which full doses
of CsA were used. Efficacy failure occurred more
frequently in study A2306 compared with study A2307,
mainly because of higher rates of BPAR in the first
6 months posttransplant [25]. These data confirm the added
benefit of IL-2 receptor antagonist induction therapy to
reduce risk of early BPAR in combination with a lower
dose of everolimus.
Infection was the most common adverse event, occurring
in 61.6% and 56.8% of patients randomized to everolimus
1.5 or 3.0 mg/d in study A2306 within the first 6 months of
treatment [25]. Interestingly, CMV disease was not com-
mon; in study A2306, it occurred in just 0.9% of patients
receiving everolimus 1.5 mg/d and in 3.2% of patients
receiving everolimus 3.0 mg/d. In the same trial, thrombo-
cytopenia occurred in 3.6% of the everolimus 1.5 mg/d
group and in 8.0% of the everolimus 3.0 mg/d group. Otheradverse events included anemia, which occurred in 18.8%
and 23.9% of the everolimus 1.5 mg/d groups of studies
A2306 and A2307, respectively, and lymphocele, the
incidence of which varied from 6.4% to 15.2% in the
4 treatment groups. In study A2306, mean total serum
cholesterol rose from 4.2 and 3.9 mmol/L at baseline to
6.6 and 6.5 mmol/L at 6 months in the everolimus 1.5 and
3.0 mg/d groups, respectively [25]. Similar elevations were
noted in study A2307 with hyperlipidemia generally
manifesting early in treatment and lipid levels stabilizing
after 2 to 3 months.
No upper limit for everolimus trough blood levels was
defined in either trial. A post hoc analysis of data from study
A2306 showed that everolimus trough blood levels up to
12 ng/mL were tolerated during 12 months of follow-up
[34]. In line with findings from studies B201 and B251,however, in which full-dose CsA was used [26], everolimus
Fig. 4. A significant reduction in CsA trough blood levels can be achieved
when used in combination with everolimus. Reproduced with permission
from Pascual [35].
trough blood levels between 3 and 8 ng/mL were found to
be optimal in efficacy and safety for patients receiving
reduced-exposure CsA.
An unanswered question remains: how low can CNI
blood levels be reduced in conjunction with everolimus
without adversely influencing efficacy and safety? Compar-
ison of the mean CsA trough blood levels of patients in
studies B201 and A2306 showed that CsA blood levels can
be reduced by at least 57% at 12 months when used in
combination with everolimus (Fig. 4) [35]. Further trials
will be needed to further study this potential for synergy.
2.4. Calcineurin inhibitor elimination
Calcineurin inhibitor withdrawal in everolimus-based
regimens is currently being validated in large clinical trials.
Studies have been conducted however with sirolimus.
Sirolimus has been used to eliminate CsA 3 months
posttransplant, with significantly improved graft function
20 patients, conversion to sirolimus led to a significant
decrease in serum creatinine from 233 F 34 to 210 F56 lmol/L after 6 months (P b .05) in 12 patients withchronic nephrotoxicity [45]. When the factors predictive of
success in patients converted from a CNI to sirolimus were
investigated, 27 (46%) of 59 patients were classed as
nonresponders based on deteriorating renal function [46].
Several baseline factors were observed that differed
significantly between responders and nonresponders, in-
cluding proteinuria, histological grade of allograft nephrop-
athy, grade of vascular intimal thickening, and number of
acute rejections before conversion. In a multivariate
analysis, only proteinuria lower than 800 mg/d before
conversion was a significant predictor of response [46]. This
finding has recently been confirmed in a study of 43 patients
converted from a CNI to sirolimus, which also identified
baseline antihypertensive therapy and serum lactate dehy-
drogenase level 1 month after conversion as independent
us hav
J. Pascual et al. / Transplantation Reviews 20 (2006) 118 7after 6, 12, 36, and 48 months in the Rapamune
Maintenance Regimen Trial [36-41] and in other studies
[42,43]. A meta-analysis of 6 sirolimus/CNI withdrawal
studies, enrolling a total of 1047 patients, showed that CNI
elimination was associated with a significant improvement
in creatinine clearance (P b .00001) at 1 year, with asignificant reduction in hypertension (P = .0006) [44].
There was, however, an 8% increased risk of acute rejection
(P = .002), although the incidences of graft loss and death
were similar in both groups. Overall, early CNI elimination
(ie, within 23 months posttransplant) is accompanied by a
reduction in the progression of chronic pathologic allograft
lesions and a lower incidence of new cases and severity of
CAN during the first year after transplantation [41]. Such
regimens may not, however, be appropriate for patients with
severe acute rejection episodes or persistent suboptimal
graft function [27].
Maintenance renal transplant patients have been con-
verted from CsA to sirolimus. In an initial study in
Fig. 5. Everolimus and sirolimpredictive factors [47].
Triple therapy with sirolimus as de novo therapy has
been compared with CsA both in combination with
azathioprine and corticosteroids in 83 patients [48], but
there was a high incidence of acute rejection (41% with
sirolimus vs 38% with CsA; NS). In a trial of similar design,
with MMF instead of azathioprine, there was a lower
incidence of acute rejection (28% with sirolimus vs 18%
with CsA) [49]. Two-year pooled data from these studies
demonstrated an improvement in graft function with
sirolimus compared with CsA (GFR, 69.3 vs 56.8 mL/min;
P b .004) [50].Sirolimus, MMF, and corticosteroids have been used
with basiliximab induction therapy to reduce the incidence
of acute rejection. When this regimen was compared with
CsA in a prospective study in 61 renal transplant recipients
there was a numerically lower incidence of acute rejection
(6% vs 17%) combined with significantly improved graft
function in the sirolimus group compared with the CsA
e similar chemical structures.
tic toxicity when used in combination with the CNIs or the
3.3.1. Dyslipidemia
Sirolimus induces dose-dependent hyperlipidemia in
30% to 50% of patients who may require concomitant
lipid-lowering medication [81,82]. A similar incidence of
hypercholesterolemia and hypertriglyceridemia has been
observed in studies of everolimus [22,25]. The alterations in
lipid metabolism appear to be related mainly to variation in
lipoprotein lipase activity and reduced catabolism of very
low-density lipoprotein apolipoprotein B100 [83]. It has
with severe refractory hyperlipidemia [33]
Lymphocele
! Treat with povidone iodine and surgical intervention as required[63-65]
Wound healing
! Surgical techniques to manage delayed fibrosis of wounds, for example,nonabsorbable sutures for muscle layers and delayed removal of skin
clips [66]
! Avoid PSIs during wound healing in patients with diabetes orobesity [67]
Maintenance patients
CAN
! Consider reducing CsA dose to counter increased creatininelevels [33,68]
! Consider withdrawing CsA (if not managed by CsA reduction)[39,41,69]
! If CsA is reduced or withdrawn, patients may require increasedeverolimus trough blood levels [33]a
! If proteinuria is N800 mg/d, do not convert to PSI therapy [46]b
Proteinuria
! Treat with ACE inhibitors and/or angiotensin receptor blockers [70,71]! Maintain everolimus blood trough levels at 38 ng/mL [33]! Minimization of CsA dose may be sufficient [72]Hypertension
! Treat with ACE inhibitors, angiotensin receptor blockers, orb-blockers [73,74]
! Consider withdrawal of CsA [36,43]! Use of calcium channel blockers may increase everolimus plasmaconcentrations [33]
Anemia
! Treat severe anemia with erythropoietin [75]! Avoid ACE inhibitors in patients who develop anemia [70]! Reduce dose of MPA agent [76]Malignancy
! Use of a PSI is recommended in patients who develop a malignancyposttransplant [77,78]
! Consider withdrawal of CsA [38,79]a Cyclosporine withdrawal from everolimus-based regimens has not
been validated in large clinical trials. There is limited experience of the use of
everolimus above trough levels of 12 ng/mL [33]. A single case study reports
everolimus trough levels above 12 ng/mL after CsAwithdrawal [80].b A phase IV study assessing 1500 mg/d proteinuria as the cutoff value
for conversion to PSI therapy is currently enrolling patients.
J. Pascual et al. / Transplantation Reviews 20 (2006) 1188mycophenolates, and those related to nonspecific immuno-
suppressive actions. Management strategies for key adverse
events are summarized in Table 3.group (creatinine clearance, 77.8 vs 64.1 mL/min at
6 months; P = .004) [51].
3. Proliferation signal inhibitors/mammalian targets of
rapamycineverolimus and sirolimus
To date, only one small head-to-head study has been
published comparing everolimus and sirolimus in 28 patients
[52]. In this study, renal function, measured by GFR, was
improved using CsA in combination with everolimus rather
than sirolimus [52]. Because of the limited analysis, a direct
comparison of the efficacy and tolerability of the 2 agents is
not possible. Based on review of the literature, an overview
of these compounds is provided below.
3.1. Pharmacology and pharmacokinetics
Everolimus and sirolimus are macrolide derivatives
with similar chemical structures, everolimus having a
2-hydroxyethyl group at position 40 of the molecule
(Fig. 5). Despite the similarities in structure, there are
important differences in the pharmacokinetic and pharma-
codynamic properties of the 2 molecules. Everolimus has a
considerably shorter half-life than sirolimus (28 vs 62 hours)
and, because of differences in regimen, everolimus reaches
steady state in 4 days, compared with 6 days for sirolimus
[33,53,54]. More detailed reviews of everolimus and
sirolimus pharmacology and pharmacokinetics can be found
in Kirchner et al [55] and Mahalati and Kahan [56].
3.2. Interaction with CsA
Although the modes of action of everolimus and sirolimus
are broadly similar, there is evidence of a difference between
these agents in their interaction with CsA. In vitro, sirolimus
has been shown to enhance CsA activity by increasing the
brain concentration of CsA, which in turn inhibits mito-
chondrial glucose metabolism and high-energy phosphate
metabolism [57,58]. Although there is no direct evidence to
link such an effect to increased neuropathologic symptoms,
drugs that inhibit glycolysis have the potential to enhance
toxicity of other agents that inhibit mitochondrial oxidation
[57]. Conversely, coadministration of everolimus and CsA
leads to a reduction in brain CsA concentration and
antagonizes the effect of CsA on glucose and high-energy
phosphate metabolism [57,59]. The clinical impact of these
different effects is not yet understood.
3.3. Adverse events
It has become evident, through extensive clinical studies,
that there are specific adverse events associated with dose-
related class actions of PSIs everolimus and sirolimus.
Additional adverse events include those related to synergis-Table 3
Guidelines for the management of adverse events in renal transplant
recipients receiving everolimus as part of their immunosuppressive regimen
De novo patients
Hyperlipidemia
! Reeducate patient regarding lifestyle changes [60,61]! Treat hypercholesterolemia with statins atorvastatin, pravastatin, orfluvastatin, as preferred [25,33,61]
! Treat hypertriglyceridemia with fibrates [60,62]! Reevaluate the risk/benefit of continued everolimus therapy in patients
J. Pascual et al. / Transplantation Reviews 20 (2006) 118 9been proposed that sirolimus indirectly up-regulates expres-
sion of the gene apo CIII, an important inhibitor of
lipoprotein lipase [27,84]. Sirolimus has also been shown
to lead to a 42% increase in free fatty acid concentrations,
thus stimulating hepatic triglyceride synthesis [85].
Hyperlipidemia should be managed in accordance with
guidelines (eg, National Kidney Foundation Kidney Disease
Outcomes Quality Initiative), focusing on both lifestyle
changes and drug treatment [60,61]. Statins and fibrates are
used to treat elevated low-density lipoprotein cholesterol
and hypertriglyceridemia, respectively [60]. Lipid-lowering
agents (mainly statins) were used in 58.9% and 66.4% of
patients receiving everolimus 1.5 and 3.0 mg/d in study
A2306, whereas in study A2307, 66.7% and 72.7% of
patients received such therapy [25]. In addition, statins were
taken by 90% of patients after heart transplantation;
although low-density lipoprotein and high-density lipopro-
tein levels were increased at 12 months, there was no
difference between the azathioprine and everolimus groups
[86]. In a study of healthy individuals given single doses of
everolimus in addition to atorvastatin or pravastatin, no
clinically significant effects on the pharmacokinetics of any
drug were noted [87], although fluvastatin has recently been
shown to improve cardiovascular outcomes in renal
transplant recipients in a large-scale clinical trial [88].
3.3.2. Myelosuppression
A higher incidence of microcytic anemia, perhaps related
to antiproliferative effects in bone marrow and reduced
incorporation of iron, has been observed with sirolimus than
with CsA or MMF in a number of studies [81,89,90]. In a
12-month study comparing everolimus and MMF (study
B201), the incidence of anemia was similar with both
agents: 34.3% in patients receiving everolimus 3.0 mg/d vs
32.1% in those receiving MMF [22].
Thrombocytopenia is common with PSIs, but seldom
clinically significant. In phase III trials with everolimus and
low-dose CsA, the incidence was 3.6% and 8.0% for
everolimus 1.5 and 3.0 mg/d, respectively, in the absence of
IL-2 receptor agonist therapy, and 3.4% and 5.8% with IL-2
receptor therapy [25]. Thrombocytopenia occurred in 37%
to 45% of sirolimus and 9% to 23% of sirolimus/CsA-
treated recipients [48,49,81,82]. The incidence, but not the
severity, of thrombocytopenia correlated with sirolimus
trough blood levels; however, this is self-limiting and the
adverse event disappears over time [27]. The incidence of
leukopenia in everolimus studies is similar to that of
thrombocytopenia, occurring in around 4% of patients in
the absence of IL-2 receptor agonist therapy, and in 3.4%
(1.5 mg/d dose) and 5.8% (3.0 mg/d) with IL-2 receptor
therapy [25].
Two hypotheses have been suggested to explain the
myelosuppression observed with PSIs. First, in vitro studies
have shown enhanced, dose-dependent, agonist-induced
platelet aggregation and granule secretion after sirolimus
exposure. Second, sirolimus inhibits signal transduction viathe gp130b chain, which is shared by cytokine receptors for
IL-11, granulocyte colony-stimulating factor, and erythro-
poietin. These molecules are all necessary for the production
of platelets and leukocytes, and sirolimus may therefore
inhibit their production [27].
Dose reduction of PSIs may be an appropriate response
to myelosuppression, but evidence for this is limited, and
active treatment with erythropoietin may become necessary
in severe anemia [90].
3.3.3. Edema
Edema of the lower and upper limbs is commonly
observed during treatment with sirolimus or everolimus
[27,91]. Prostacyclin release from endothelial cells, stimu-
lated by sirolimus, leads to vasodilatation [92], suggesting
that edema may be related to capillary leakage, as has been
observed in sirolimus-treated lung transplant recipients and
patients with psoriasis [93,94]. In addition to limb edema,
bilateral eyelid edema has been observed both in de novo
and maintenance transplant recipients receiving sirolimus
and everolimus [91,95,96].
3.3.4. Arthralgia
Arthralgia is a common adverse event occurring with
both drugs. In a study comparing sirolimus and CsA,
arthralgia was reported in 20% of patients in the sirolimus
group at 12 months, but was not reported in the CsA group
[48]. In a separate study comparing sirolimus and azathio-
prine, arthralgia was listed as a cause of study discontinu-
ation in the sirolimus group [81]. Arthralgia has also been
reported in patients in the everolimus A2306 study [91]. The
cause of this phenomenon is, however, not clear.
3.3.5. Impaired wound healing
The antiproliferative effects of PSIs have been associated
with a high incidence of wound healing problems. Delayed
healing of lymphatic channels divided during surgery and
a reduced fibrotic reaction contribute to an increased
incidence of lymphocele [97]. Compared with azathioprine,
sirolimus 5 mg/d is associated with an increased incidence
of postoperative lymphoceles [81], and similar results have
been seen with sirolimus in combination with CsA or
tacrolimus [98]. In studies A2306 and A2307, the incidence
of lymphocele at 6 months posttransplant was 15.2% and
10.3% with everolimus 1.5 mg/d, and 6.4% and 7.2% with
everolimus 3.0 mg/d, respectively [25] (Table 4). Potential
risk factors for delayed healing include recipient age,
presence of diabetes, and living vs cadaveric donor
[66,67]. In addition, thymoglobulin induction, body mass
index greater than 32 kg/m2, and a cumulative sirolimus
dose greater than 35 mg over the first 5 days of treatment
were all significantly associated with impaired wound
healing [98]. When the loading dose of sirolimus was
eliminated from a study of steroid-free maintenance
regimens in 239 patients, the incidence of wound healing
problems decreased [99]. Excellent surgical technique, such
hibiting renal tubular cell regeneration and by increasing
enal tubular cell loss by apoptosis [103].
.3.7. Proteinuria
In chronic glomerular diseases, proteinuria is an impor-
nt marker of the risk of a progressive, irreversible decline
GFR [104], and proteinuria levels greater than 800 mg/d
ave a negative correlation with outcome if treatment of
atients is converted from CNI to sirolimus [46]. Minimi-
ation of proteinuria is, therefore, a key goal in the treatment
f chronic kidney disease [70]. In 50 renal transplant
ecipients with CAN who were switched from CNIs to
irolimus, 64% developed marked proteinuria, with ne-
hrotic syndrome in around half of these patients [105],
atients with preexisting proteinuria having a higher
ecurrence rate. In 1 study of patients with existing CAN,
2% had no proteinuria (b150 mg/d) at the time ofonversion from CNI to sirolimus [47]. However, 19.4%
f patients had proteinuria greater than 1000 mg/d at 1-year
inhibitor regimens are safe and effective in the long-term
treatment of hypertension in renal transplant recipients
[73,74]. The long-term benefits of using calcium channel
blockers are not well defined in renal transplant recipients,
and there may be a possible interaction between agents
such as verapamil or diltiazem with everolimus, resulting in
an increase in everolimus levels [33]. Studies with
sirolimus have shown a significant reduction in blood
pressure after CNI elimination, demonstrating another
possible approach [36,43].
4. Proliferation signal inhibitors in current
clinical practice
4.1. Patient selection
In combination with CsA and corticosteroids, everolimus
is currently approved for the prophylaxis of organ rejection
in adult patients at low-to-moderate immunologic risk
s and
/d)a
/d)a
/d)b
/d)b
.0 mg
.0 mg/d) 154
mus
blood
blood
/d)
/d)
J. Pascual et al. / Transplantation Reviews 20 (2006) 11810r
in
r
3
ta
in
h
p
z
o
r
s
p
p
r
8
c
oas meticulous ligation of transected lymphatic channels,
delayed removal of skin clips, and the use of nonabsorbable
sutures, may reduce wound complications. Management of
posttransplant lymphocele remains the subject of debate.
Milder cases may be self-limiting or respond to instillation
of povidone iodine [63], although laparoscopic drainage
may be required [64,65].
3.3.6. Renal dysfunction
Experimental data demonstrate that the PSI class of
drugs has limited direct toxic effects on the kidney;
however, sirolimus and everolimus clearly augment CNI
toxicity partly through the effect shown with sirolimus,
which increases tissue CsA concentrations [100,101]
and may also be related to its effects on glucose meta-
bolism [102].
There has been concern that PSIs delay the recovery of
enal function after acute tubular necrosis (ATN) possibly by
Table 4
Incidence of wound healing problems and lymphoceles in trials of sirolimu
Study Duration (mo) Agent
Study A2306 [25] 6 Everolimus (1.5 mg
Everolimus (3.0 mg
Study A2307 [25] 6 Everolimus (1.5 mg
Everolimus (3.0 mg
Kahan [81] 12 CsA + sirolimus (2
CsA + sirolimus (5
CsA + azathioprine
Ciancio et al [98] 12 Tacrolimus + siroli
Tacrolimus + MMF
CsA + sirolimus
Studies B201 and B251 12 Everolimus (trough
Everolimus (trough
Study B201 [23] 36 Everolimus (1.5 mg
Everolimus (3.0 mg
MMF (2.0 g/d)
a In combination with reduced-dose CsA.b In combination with reduced-dose CsA and basiliximab induction.
4 P b .001 vs azathioprine.postconversion and this increased to 20.6% at 2 years [47].
Experimental laboratory evidence suggests that sirolimus
may lead to an increase in proteinuria through interference
with normal tubular epithelial cell compensatory mecha-
nisms [106]. It is of interest that there was no excess de novo
proteinuria reported in any of the randomized phase II and
III studies of sirolimus [27]. There is no evidence available
for everolimus in phase III studies as data on proteinuria
were not routinely collected. However, the incidence,
mechanism, and management of proteinuria in patients
receiving everolimus are currently being investigated.
Angiotensin-converting enzyme (ACE) inhibitors and
angiotensin II receptor blockers may have potential clinical
utility for the management of both hypertension and
proteinuria in patients receiving everolimus [71,104]. This
is an area that requires further investigation especially in
relation to exacerbating anemia [107].
Nevertheless, clinical trial data suggest that ACE
3
16 6
6 4
14 4
level, 3 ng/mL) 20 20
level, 8 ng/mL) 12 16
9
12
4 everolimus
Lymphocele (%) Wound dehiscence (%)
15.2
6.4
10.3
7.2
/d) 12
J. Pascual et al. / Transplantation Reviews 20 (2006) 118 11receiving an allogeneic renal or cardiac transplant. Ever-
olimus should not be used with full doses of CsA beyond
1 month posttransplantation.
4.1.1. bOld-for-oldQ transplantationIn recent years, the age of patients receiving renal
transplants has increased, with around one third being older
than 55 years [108,109]. Similarly, the proportion of donors
aged older than 55 years has increased. There has therefore
been a trend toward age matching of donor and recipient to
ensure appropriate use of donated organs [80,108,110,111].
This means that the current estimated potential for bold-for-old Q transplantation is approximately 30% of all trans-plants. Older organs are at greater risk of delayed graft
functioning, CAN and CNI toxicity, and it has been
suggested that they should be targeted for CNI minimization
[80,110,112].
4.1.2. Patients younger than 15 years
Everolimus is not currently indicated in pediatric
patients, but dosing, efficacy, and safety data in this patient
group are beginning to emerge [113,114].
4.1.3. Malignancy
Everolimus and sirolimus interrupt the PI3K/Akt signal-
ing pathway, which plays a critical role in regulating cell
proliferation, survival, mobility, and angiogenesis [115].
Tumors that rely on overactivity of the PI3K/Akt pathway
for growth may therefore be susceptible to this class of
agent. In vitro and in vivo studies have shown that growth
of a number of tumor cell lines can be slowed or prevented
with sirolimus, including those derived from liver [116,117],
breast [118], pancreas [119], and ovary [120], as well as
myeloid and lymphocytic leukemia cell lines [121,122]. In a
breast cancer cell line, sirolimus has also been shown to
restore sensitivity to tamoxifen [123].
Use of everolimus in vitro and in vivo has yielded
similar results to those with sirolimus. A combination of
everolimus and epidermal growth factor receptor/vascular
endothelial growth factor receptor 2 leads to inhibition
of glioblastoma growth [124], and everolimus has also
been shown to reverse Akt-dependent prostate intra-
epithelial neoplasia [125]. In a primary cell culture derived
from patients with acute myeloid leukemia, everolimus
enhanced the activity of the PI3 kinase inhibitor,
LY294002 [126]. Everolimus has also been shown to
inhibit the growth of transformed B lymphocytes [127] and
a cell line derived from a patient with posttransplant
lymphoproliferative disorder [128]. In a rat pancreatic
tumor model, everolimus demonstrated significant, dose-
dependent antitumor activity that was similar to that
observed with the cytotoxic agent 5-fluorouracil [129]. In
a study combining everolimus with the DNA-damaging
agent cisplatin, everolimus was shown to inhibit expres-
sion of p21, thus increasing the susceptibility of tumor
cells to apoptosis [130].In phase III studies of sirolimus, no increased incidence
of malignancies has been observed compared with either
placebo or azathioprine when combined with CsA and
corticosteroids [81,82]. During a 3-year study of CNI
elimination in sirolimus-treated patients, those in whom
CNI therapy was stopped had a numerically lower incidence
of malignancies compared with those remaining on CNI
(5.6% vs 11.2%) [37]. When results were pooled from
5 phase II and III studies, the overall incidence of
malignancies in patients receiving a combination of CsA
and sirolimus was found to be similar to that in patients
receiving CsA or azathioprine, whereas early elimination of
CsA was associated with a reduced risk of malignancies
[79]. In a multicenter, open-label study of 167 patients
enrolled from previous sirolimus studies (mean exposure to
sirolimus, 1526 days), malignancies were reported in 11
patients receiving CsA and sirolimus; none of the patients in
whom CsA had been eliminated experienced malignancies
[38]. In a study of 430 patients randomized at 3 months after
renal transplantation to continue sirolimus and CsA or have
CsA withdrawn, CNI-free therapy significantly reduced the
incidence of nonskin cancer at 5 years posttransplant [131].
In studies of everolimus, the incidence of malignancies was
lowafter 36 months of treatment, the incidence of
malignancies was 5.2%, 4.5%, and 4.6% in the 1.5 mg/d
everolimus, 3.0 mg/d everolimus, and MMF group, respec-
tively (study B201) [23], and 4.7%, 5.2%, and 6.1%,
respectively (study B251) [24]. After 24 months of
treatment with reduced CsA doses, the proportion of
patients experiencing malignancies was even lower [30].
Conversion from CsA to sirolimus has recently been
suggested as a potential method of treating malignancies in
transplant recipients without increasing the risk of graft
rejection. For example, 2 renal transplant recipients with
Kaposi sarcoma underwent conversion from CsA to siroli-
mus, with complete regression of their Kaposi sarcoma
lesions [77]. These beneficial effects on Kaposi sarcoma
were further explored in a prospective study in 15 renal
transplant recipients who were switched from CsA to
sirolimus [78]. Three months after conversion, all Kaposi
sarcoma lesions had disappeared, and remission was con-
firmed by histopathology at 6 months. There were no
acute episodes of rejection or changes in graft function.
Beneficial effects of sirolimus in liver transplant recipients
with hepatocellular carcinoma have also been reported,
in both decreased tumor recurrence and remission of
metastases [132,133].
4.2. Everolimus dosing and administration
As has been demonstrated in clinical trials, everolimus is
an effective immunosuppressant when given immediately
after renal transplantation in combination with CsA,
corticosteroids and, possibly, IL-2 receptor antagonist
induction therapy [21,25]. Suggested algorithms for ever-
olimus treatment are provided for de novo (Fig. 6) and
maintenance (Fig. 7) renal transplant recipients.
J. Pascual et al. / Transplantation Reviews 20 (2006) 118124.2.1. De novo patients
In de novo renal transplant recipients, everolimus should
be initiated at a dose of 0.75 mg BID dose adjustment to
ensure trough blood levels of 3 to 8 ng/mL [26,34] (Fig. 6).
Straightforward TDM can now be achieved using an
immunoassay (Innofluor Certican, Seradyn Inc, Indian-
apolis, Ind). Lower CsA C2 levels can be targeted in the
weeks after transplantation with IL-2 receptor antibody
Fig. 6. Treatment guidelines for the use of everolimus in de novo renal transplan
stable at with down-titration of CsA concentrations, with CsA C0 levels in t
therapy, CsA exposure may be minimized further: CsA C2 levels 500 to 700
[25,33]. yCsA withdrawal from everolimus-based regimens is currently being veverolimus above trough levels of 12 ng/mL [33]. A single case study reports e
indicates twice daily.induction [25]. Table 5 provides insights from a single
center experience on the practical use of low-dose CsA and
everolimus in renal transplantation.
4.2.2. Maintenance patients
Based on studies with sirolimus, everolimus could allow
CsA minimization or elimination [38,44,46] (Fig. 7).
Cyclosporine has been reduced or withdrawn in progres-
t recipients. Everolimus trough blood levels have been reported to remain
he range of 25 to 50 ng/mL [26,134,135]. *With basiliximab induction
ng/mL in weeks 0 to 8 and 350 to 450 ng/mL in week 9 to month 12
alidated in large clinical trials. zThere is limited experience of the use ofverolimus trough levels above 12 ng/mL after CsA withdrawal [80]. b.i.d.
Fig. 7. Treatment guidelines for the use of everolimus in maintenance renal transplant recipients receiving CNIs. CNI can be reduced in a stepwise progression
of approximately 25% each step; however, abrupt cessation of CNI is also used in clinical practice. zRange 800 to 1500 mg/d; published data from 1 study [46]recommends 800 mg/d as the cutoff point for proteinuria; however, an ongoing phase IV study is assessing 1500 mg/d proteinuria as the cutoff value for
conversion to PSI therapy. yThere is limited experience of the use of everolimus above trough levels of 12 ng/mL [33]. Clinical opinion (see Table 5) suggeststhat lower everolimus exposure may allow for increased tolerability. Everolimus levels of 6 to 12 ng/mL are currently being evaluated in ongoing phase IV
studies. *CsA withdrawal from everolimus-based regimens is currently being validated in large clinical trials.
J. Pascual et al. / Transplantation Reviews 20 (2006) 118 13
insig
[80] p
eg, y
of thi
toxic
lder p
e to CNI-related nephrotoxicity, not least because older organs tend to have worse
renal
re to
case
to 40
sA. G
splant
ld-for
from
us an
l tran
receiv
J. Pascual et al. / Transplantation Reviews 20 (2006) 11814Table 5
Low-dose CsA and everolimus strategies in de novo renal transplantation
Q: Which renal transplant patients should be considered for PSI therapy?
A: Everolimus offers potential for both CsA minimization and withdrawal
! De novo patients at high risk of suboptimal renal function! Patients for whom very long-term immunosuppression will be required (! Patients at risk for CMV infection (it is associated with a low incidence! In the maintenance setting, patients at risk for or exhibiting CNI-related
Q: Can one define patients at high risk of suboptimal graft function?
A: In an effort to expand the donor pool, it is becoming common for o
transplantation [80,137]. However, these patients may be more susceptibl
function than younger organs [112,136].
Q: How may everolimus be used to reduce CNI exposure and to optimize
A: Two recent clinical trials show that everolimus allows CsA exposu
immunosuppressive efficacy and good renal function [25]. Two long-term
recently published [80].
! Case 1: Everolimus 0.75 mg BID allowed a reduction in CsA C2 levelsstabilized at around 1.7 mg/dL [80].
! Case 2: Everolimus 1.5 mg BID was combined with reduced-exposure Cpeaking at 3.8 mg/dL before CsAwas withdrawn [80]. By 2 years posttran
everolimus and low-dose steroids [80].
Q: What is an acceptable posttransplant mean serum creatinine level for boA: Previous experience from Spain shows that patients receiving a kidney
2.06 mg/dL [112]. Case 1 above, in which a patient treated with everolim
2 years posttransplant represents a good outcome for an old-for-old rena
Q: What CsA C2 levels optimize long-term renal graft function in patientssive steps of approximately 25% over 4 weeks; how-
ever, immediate cessation of CNIs has also been used in
clinical practice.
In the maintenance phase of treatment, there are currently
few data in patients with CsAC2 levels lower than 350 ng/mL
(trough blood (C0) 50 ng/mL). Initial experience suggests
that CsA can be discontinued in selected patients receiving
everolimus [80], although the dose of everolimus then needs
to be increased to compensate for the pharmacokinetic
interaction that leads to a 2- to 3-fold decrease in everolimus
blood levels when CsA is withdrawn [15]. After CsA
withdrawal, initial clinical experience suggests that ever-
olimus trough blood levels of 10 to 15 ng/mL may be needed
when using everolimus and corticosteroids only [80], but that
lower trough blood levels may be required if also using an
MPA agent.
4.1.3. Future study of everolimus
There is an ongoing phase IV clinical trial program for
everolimus to refine the use of everolimus in clinical
practice [7], including a delayed start to permit wound
healing, prospective use in maintenance renal transplant
patients, and the ability to facilitate CNI minimization and
withdrawal. Everolimus is currently licensed for use in
combination with low-dose CsA, but tacrolimus is also
widely used in renal transplant recipients. At least 1
pharmacokinetic phase II and 2 large phase III trials are
exploring the combination of tacrolimus and everolimus in
de novo kidney transplantation. Everolimus has also been
shown to reduce the severity and incidence of cardiac
allograft vasculopathy posttransplantation in heart transplan
recipients, perhaps by inhibiting proliferation of smooth
muscle cells [86]. This is an additional area for future
investigation in the renal transplant population.
5. Conclusions
There is good clinical trial evidence to support the
efficacy and tolerability of everolimus in renal transplanta-
tion. Clinical trial data indicate that everolimus can facilitate
minimization of CsA exposure, but ongoing clinical trials
and clinical practice will help to further refine its therapeutic
role. Everolimus is associated with several class-specific
adverse events (eg, hyperlipidemia), but experience to date
A: Minimization of CsA exposure to ensure C2 levels less than 400 ng/mL by 6 months posttransplant is desirable [80]. Cyclosporine C2 exposure levels o
350450 ng/mL from week 13 posttransplantation, or week 9 posttransplantation if using basiliximab (Simulect) induction therapy, are recommended
[25,33].
Q: When is complete withdrawal of CNIs appropriate?
A: CNI withdrawal is generally only necessary if the patient is experiencing nephrotoxicity or other serious adverse events that do not respond to CNI dose
minimization [80]. In our experience, if CNIs are withdrawn, everolimus dose should be increased to achieve blood trough levels of 812 ng/mL, but there
are no clinical trials to support this strategy.
Q: Which specific adverse events associated with use of everolimus are most troublesome?
A: Patients may experience hyperlipidemia during everolimus therapy, which can generally be controlledwith statins [33,80]. Early after transplantation, lymphocele
or wound dehiscence can occur, but they are usually not severe [33]. Lymphocele may be self-limiting or responsive to povidone iodine treatment [91].
Q: How should everolimus be used in combination with mycophenolate therapy in maintenance renal transplant recipients?
A: It is advisable to closely monitor patients receiving everolimus, MPA, and steroids to ensure that they do not become over-immunosuppressed or anemic
[138]. The use of low levels of everolimus (38 ng/mL) and MMF (1 g) should be considered. Formal study in clinical trials is needed to explore this strategyt
f
.function?
be reduced in de novo renal transplant recipients, while maintaining
studies of bold-for-oldQ renal transplants from one of these trials have been
0 ng/mL after 4 months posttransplant [80]. Serum creatinine subsequently
raft function deteriorated despite CsA minimization, with serum creatinine
, serum creatinine had stabilized at 2.5 mg/dL with the patient maintained on
-oldQ transplant patients?an elderly donor have mean 12-month serum creatinine levels around
d reduced-dose CsA has a stable serum creatinine level of 1.7 mg/dL up to
splant [80].
ing everolimus?hts from Hospital Ramon y Cajal, Madrid, Spain
articularly in:
oung patients) [136]
s infection [22])
ities or CAN.
atients (ie, N55 years) to receive older kidneysso-called bold-for-oldQ
microemulsion in cynomolgus monkey kidney allotransplantation.
the novel rapamycin analog, SDZ RAD, to rat lung allograft
recipients: potentiation of immunosuppressive efficacy and improve-
J. Pascual et al. / Transplantation Reviews 20 (2006) 118 15ment of tolerability of staggered versus simultaneous treatment.
Transplantation 1999;67:956 -62.
[13] Lutz J, Zou H, Liu S, Antus B, et al. Apoptosis and treatment of
chronic allograft nephropathy with everolimus. Transplantation
2003;76:508 -15.
[14] Neumayer HH, Paradis K, Korn A, et al. Entry-into-human study
with the novel immunosuppressant SDZ RAD in stable renal
transplant recipients. Br J Clin Pharmacol 1999;48:694 -703.
[15] Kovarik JM, Kalbag J, Figueiredo J, et al. Differential influence of
two cyclosporine formulations on everolimus pharmacokinetics: a
clinically relevant pharmacokinetic interaction. J Clin Pharmacol
2002;42:95 -9.Transplantation 2000;69:737 -42.
[11] Viklicky O, Zou H, Muller V, et al. SDZ-RAD prevents manifes-
tation of chronic rejection in rat renal allografts. Transplantation
2000;69:497-502.
[12] Hausen B, Boeke K, Berry GJ, et al. Coadministration of Neoral andsuggests that these can be managed. Investigation of
the antineoplastic activity of everolimus is anticipated given
the positive effects that have been documented for sirolimus
especially in patients with Kaposi sarcoma. This class
of agent has yet to find its true role, but the potential
to maintain immunosuppression without the twin penalties
of nephrotoxicity and malignancy will provide the
incentive to refine our clinical use of both sirolimus
and everolimus.
Acknowledgement
The authors thank Dr J Chapman for review of the
manuscript.
References
[1] UNOS. United Network for Organ Sharing. http://www.optn.org/
AR2004/111a_dh.htm [Last accessed: June 2005].
[2] Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working clas-
sification of renal allograft pathology. Kidney Int 1999;55:713-23.
[3] Nashan B. The role of Certican (everolimus, RAD) in the many
pathways of chronic rejection. Transplant Proc 2001;33:3215-20.
[4] Nankivell BJ, Borrows RJ, Fung CL, et al. The natural history of
chronic allograft nephropathy. N Engl J Med 2003;349:2326 -33.
[5] Schuler W, Sedrani R, Cottens S, et al. SDZ RAD, a new rapamycin
derivative: pharmacological properties in vitro and in vivo.
Transplantation 1997;64:36 -42.
[6] Schuurman HJ, Pally C, Weckbecker G, et al. C. SDZ RAD inhibits
cold ischemia-induced vascular remodeling. Transplant Proc
1999;31:1024-5.
[7] Neumayer HH. Introducing everolimus (Certican) in organ trans-
plantation: an overview of preclinical and early clinical develop-
ments. Transplantation 2005;79:S72-5.
[8] Schuurman HJ, Cottens S, Fuchs S, et al. SDZ RAD, a new
rapamycin derivative: synergism with cyclosporine. Transplantation
1997;64:32-5.
[9] Schuurman HJ, Schuler W, Ringers J, et al. The macrolide SDZ RAD
is efficacious in a nonhuman primate model of allotransplantation.
Transplant Proc 1998;30:2198-9.
[10] Schuurman HJ, Ringers J, Schuler W, et al. Oral efficacy of the
macrolide immunosuppressant SDZ RAD and of cyclosporine[16] Kovarik JM, Dantal J, Civati G, et al. Influence of delayed initiation
of cyclosporine on everolimus pharmacokinetics in de novo renal
transplant patients. Am J Transplant 2003;3:1576 -80.
[17] Kirchner GI, Winkler M, Mueller L, et al. Pharmacokinetics of SDZ
RAD and cyclosporin including their metabolites in seven kidney
graft patients after the first dose of SDZ RAD. Br J Clin Pharmacol
2000;50:449-54.
[18] Kahan BD, Wong RL, Carter C, et al. A phase I study of a 4-week
course of SDZ-RAD (RAD) in quiescent cyclosporine-prednisone
treated renal transplant recipients. Transplantation 1999;68:1100-6.
[19] Kovarik JM, Kahan BD, Kaplan B, et al. Longitudinal assessment of
everolimus in de novo renal transplant recipients over the first post-
transplant year: pharmacokinetics, exposure-response relationships,
and influence on cyclosporine. Clin Pharmacol Ther 2001;69:48-56.
[20] Kahan BD, Kaplan B, Lorber MI, et al. RAD in de novo renal
transplantation: comparison of three doses on the incidence and
severity of acute rejection. Transplantation 2001;71:1400-6.
[21] Nashan B, Curtis J, Ponticelli C, et al. Everolimus and reduced-
exposure cyclosporine in de novo renal-transplant recipients: a three-
year phase II, randomized, multicenter, open-label study. Transplan-
tation 2004;78:1332-40.
[22] Vtko S, Margreiter R, Weimar W, et al. Everolimus (Certican)
12-month safety and efficacy versus mycophenolate mofetil in de
novo renal transplant recipients. Transplantation 2004;78:1532-40.
[23] Vtko S, Margreiter R, Weimar W, et al. Three-year efficacy and
safety results from a study of everolimus versus mycophenolate
mofetil in de novo renal transplant patients. Am J Transplant
2005;5:2521-30.
[24] Lorber MI, Mulgaonkar S, Butt KMH, et al. Everolimus versus
mycophenolate mofetil in the prevention of rejection in de novo renal
transplant recipients: a 3-year randomized, multicenter, phase III
study. Transplantation 2005;80:244-52.
[25] Vtko S, Tedesco H, Eris J, et al. Everolimus with optimized
cyclosporine dosing in renal transplant recipients: 6-month safety
and efficacy results of two randomized studies. Am J Transplant
2004;4:626-35.
[26] Lorber MI, Ponticelli C, Whelchel J, et al. Therapeutic drug
monitoring for everolimus in kidney transplantation using 12-month
exposure, efficacy, and safety data. Clin Transplant 2005;19:145 -52.
[27] Kuypers DR. Benefit-risk assessment of sirolimus in renal trans-
plantation. Drug Saf 2005;28:153 -81.
[28] Holmes M, Chilcott J, Walters S, et al. Economic evaluation of
everolimus versus mycophenolate mofetil in combination with
cyclosporine and prednisolone in de novo renal transplant recipients.
Transpl Int 2004;17:182-7.
[29] Leone J, Vtko S, Whelchel J, et al. Excellent graft function in de
novo kidney transplant recipients treated with Certican, Simulect and
reduced Neoral exposure: 24 month results. Am J Transplant
2005;5(Suppl 11):A1010.
[30] Pascual J, Cambi V, Dissegna D, et al. Efficacy and safety of 2 doses
of everolimus combined with reduced dose Neoral in de novo kidney
transplant recipients: 24 months analysis. Am J Transplant
2005;5(Suppl 11):A1010.
[31] Magee J, Tedesco H, Pascual J, et al. Efficacy and safety of 2 doses
of everolimus combined with reduced-dose Neoral in de novo kidney
transplant recipients: 12 month analysis. Am J Transplant 2004;
4(Suppl 8):296 [abstract 504].
[32] Whelchel J, Vitko S, Eris J, et al. Excellent graft function in de novo
kidney transplant recipients treated with Certican, Simulect and
reduced Neoral exposure. 12-month results. Am J Transplant
2004;4(Suppl 8):297 [abstract 507].
[33] Novartis Pharma AG. Certican summary of product characteristics.
Basel7 Novartis Pharma AG; 2003.
[34] Kovarik JM, Tedesco H, Pascual J, et al. Everolimus therapeutic
concentration range defined from a prospective trial with reduced-
exposure cyclosporine in de novo kidney transplantation. Ther Drug
Monit 2004;26:499-505.
J. Pascual et al. / Transplantation Reviews 20 (2006) 11816[35] Pascual J. Concentration-controlled everolimus (Certican): combi-
nation with reduced dose calcineurin inhibitors. Transplantation
2005;79:S76 -9.
[36] Johnson RWG, Kreis H, Oberbauer R, et al. Sirolimus allows
early cyclosporine withdrawal in renal transplantation resulting in
improved renal function and lower blood pressure. Transplantation
2001;72:777 -86.
[37] Kreis H, Oberbauer R, Campistol JM, et al. Long-term benefits with
sirolimus-based therapy after early cyclosporine withdrawal. J Am
Soc Nephrol 2004;15:809 -17.
[38] Morales JM, Campistol JM, Kreis H, et al. Sirolimus-based therapy
with or without cyclosporine: long-term follow-up in renal transplant
patients. Transplant Proc 2005;37:693-6.
[39] Mota A, Arias M, Taskinen EI, et al. Sirolimus-based therapy
following early cyclosporine withdrawal provides significantly
improved renal histology and function at 3 years. Am J Transplant
2004;4:953 -61.
[40] Oberbauer R, Segoloni G, Campistol JM, et al. Early cyclosporine
withdrawal from a sirolimus-based regimen results in better renal
allograft survival and renal function at 48 months after transplanta-
tion. Transpl Int 2005;18:22 -8.
[41] Ruiz JC, Campistol JM, Grinyo JM, et al. Early cyclosporine a
withdrawal in kidney-transplant recipients receiving sirolimus
prevents progression of chronic pathologic allograft lesions. Trans-
plantation 2004;78:1312-8.
[42] Baboolal K. A phase III prospective, randomized study to evaluate
concentration-controlled sirolimus (rapamune) with cyclosporine
dose minimization or elimination at 6 months in de novo renal
allograft recipients. Transplantation 2003;75:1404-8.
[43] Gonwa TA, Hricik DE, Brinker K, et al. Improved renal function in
sirolimus-treated renal transplant patients after early cyclosporine
elimination. Transplantation 2002;74:1560-7.
[44] Mulay AV, Hussain N, Fergusson D, et al. Calcineurin inhibitor
withdrawal from sirolimus-based therapy in kidney transplantation: a
systematic review of randomized trials. Am J Transplant 2005;5:
1748-56.
[45] Dominguez J, Mahalati K, Kiberd B, et al. Conversion to rapamycin
immunosuppression in renal transplant recipients: report of an initial
experience. Transplantation 2000;70:1244-7.
[46] Diekmann F, Budde K, Oppenheimer F, et al. Predictors of success in
conversion from calcineurin inhibitor to sirolimus in chronic
allograft dysfunction. Am J Transplant 2004;4:1869-75.
[47] Bumbea V, Kamar N, Ribes D, et al. Long-term results in renal
transplant patients with allograft dysfunction after switching from
calcineurin inhibitors to sirolimus. Nephrol Dial Transplant 2005;
20:2517-23.
[48] Groth CG, B7ckman L, Morales JM, et al. Sirolimus (rapamycin)based therapy in human renal transplantation: similar efficacy and
different toxicity compared with cyclosporine. Sirolimus European
Renal Transplant Study Group. Transplantation 1999;67:1036-42.
[49] Kreis H, Cisterne JM, Land W, et al. Sirolimus in association with
mycophenolate mofetil induction for the prevention of acute graft
rejection in renal allograft recipients. Transplantation 2000;69:
1252-60.
[50] Morales JM, Wramner L, Kreis H, et al. Sirolimus does not exhibit
nephrotoxicity compared to cyclosporine in renal transplant recipi-
ents. Am J Transplant 2002;2:436 -42.
[51] Flechner SM, Goldfarb D, Modlin C, et al. Kidney transplantation
without calcineurin inhibitor drugs: a prospective, randomized trial
of sirolimus versus cyclosporine. Transplantation 2002;74:1070-6.
[52] Kamar N, Allard J, Ribes D, et al. Assessment of glomerular and
tubular functions in renal transplant patients receiving cyclosporine
A in combination with either sirolimus or everolimus. Clin Nephrol
2005;63:80 -6.
[53] Ferron GM, Mishina EV, Zimmerman JJ, et al. Population
pharmacokinetics of sirolimus in kidney transplant patients. Clin
Pharmacol Ther 1997;61:416-28.[54] MacDonald A, Scarola J, Burke JT, et al. Clinical pharmacokinetics
and therapeutic drug monitoring of sirolimus. Clin Ther 2000;
22(Suppl B):B101-21.
[55] Kirchner GI, Meier-Wiedenbach I, Manns MP. Clinical pharmaco-
kinetics of everolimus. Clin Pharmacokinet 2004;43:83-95.
[56] Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin
Pharmacokinet 2001;40:573-85.
[57] Serkova N, Jacobsen W, Niemann CU, et al. Sirolimus, but not the
structurally related RAD (everolimus), enhances the negative effects
of cyclosporine on mitochondrial metabolism in the rat brain. Br J
Pharmacol 2001;133:875-85.
[58] Serkova N, Litt L, James TL, et al. Evaluation of individual and
combined neurotoxicity of the immunosuppressants cyclosporine
and sirolimus by in vitro multinuclear NMR spectroscopy.
J Pharmacol Exp Ther 1999;289:800-6.
[59] Serkova N, Litt L, Leibfritz D, et al. The novel immunosuppressant
SDZ-RAD protects rat brain slices from cyclosporine-induced
reduction of high-energy phosphates. Br J Pharmacol 2000;129:
485 -92.
[60] Kasiske B, Cosio FG, Beto J, et al. Clinical practice guidelines for
managing dyslipidemias in kidney transplant patients: a report from
the Managing Dyslipidemias in Chronic Kidney Disease Work
Group of the National Kidney Foundation Kidney Disease Outcomes
Quality Initiative. Am J Transplant 2004;4(Suppl 7):13 -53.
[61] Mathis AS, Dave N, Knipp GT, et al. Drug-related dyslipidemia after
renal transplantation. Am J Health Syst Pharm 2004;61:565-85.
[62] Blum CB. Effects of sirolimus on lipids in renal allograft recipients:
an analysis using the Framingham risk model. Am J Transplant
2002;2:551 -9.
[63] Teruel JL, Escobar EM, Quereda C, et al. A simple and safe method
for management of lymphocele after renal transplantation. J Urol
1983;130:1058-9.
[64] Bischof G, Rockenschaub S, Berlakovich G, et al. Management
of lymphoceles after kidney transplantation. Transpl Int 1998;11:
277 -80.
[65] Fuller TF, Kang SM, Hirose R, et al. Management of lymphoceles
after renal transplantation: laparoscopic versus open drainage. J Urol
2003;169:2022-5.
[66] Flechner SM, Zhou L, Derweesh I, et al. The impact of sirolimus,
mycophenolate mofetil, cyclosporine, azathioprine, and steroids on
wound healing in 513 kidney-transplant recipients. Transplantation
2003;76:1729-34.
[67] Knight RJ, Villa M, Welsh M, et al. Risk factors for impaired wound
healing in sirolimus treated renal transplant recipients. Am J
Transplant 2003;3(Suppl 5):481.
[68] Hariharan S, Peddi VR, Savin VJ, et al. Recurrent and de novo renal
diseases after renal transplantation: a report from the renal allograft
disease registry. Am J Kidney Dis 1998;31:928-31.
[69] Chapman JR. Optimizing the long-term outcome of renal transplants:
opportunities created by sirolimus. Transplant Proc 2003;35:67 -72.
[70] Wilmer WA, Rovin BH, Hebert CJ, Rao SV, Kumor K, Hebert LA.
Management of glomerular proteinuria: a commentary. J Am Soc
Nephrol 2003;14:3217-32.
[71] Muirhead N, House A, Hollomby DJ, et al. Effect of valsartan on
urinary protein excretion and renal function in patients with chronic
renal allograft nephropathy. Transplant Proc 2003;35:2412-4.
[72] Mourad G, Vela C, Ribstein J, et al. Long-term improvement in renal
function after cyclosporine reduction in renal transplant recipients
with histologically proven chronic cyclosporine nephropathy. Trans-
plantation 1998;65:661 -7.
[73] Hausberg M, Barenbrock M, Hohage H, et al. ACE inhibitor versus
b-blocker for the treatment of hypertension in renal allograftrecipients. Hypertension 1999;33:862-8.
[74] Suwelack B, Kobelt V, Erfmann M, et al. Long-term follow-up of
ACE-inhibitor versus beta-blocker treatment and their effects on
blood pressure and kidney function in renal transplant recipients.
Transpl Int 2003;16:313 -20.
J. Pascual et al. / Transplantation Reviews 20 (2006) 118 17[75] Lorenz M, Kletzmayr J, Perschl A, et al. Anemia and iron
deficiencies among long-term renal transplant recipients. J Am Soc
Nephrol 2002;13:794-7.
[76] Winkelmayer WC, Kewalramani R, Rutstein M, et al. Pharmacoe-
pidemiology of anemia in kidney transplant recipients. J Am Soc
Nephrol 2004;15:1347-52.
[77] Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to
sirolimus: a successful treatment for posttransplantation Kaposis
sarcoma. Transplantation 2004;77:760 -2.
[78] Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposis
sarcoma in renal-transplant recipients. N Engl J Med 2005;352:
1317-23.
[79] Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in
sirolimus-treated renal transplant recipients: results from five
multicenter studies. Clin Transplant 2004;18:446-9.
[80] Pascual J, Marcen R, Ortuno J. Clinical experience with everolimus
(Certican) in elderly recipients: the bold-for-oldQ concept. Transplan-tation 2005;79:S85-8.
[81] Kahan BD. Efficacy of sirolimus compared with azathioprine for
reduction of acute renal allograft rejection: a randomised multicentre
study. The Rapamune US Study Group. Lancet 2000;356:194-202.
[82] MacDonald AS. A worldwide, phase III, randomized, controlled,
safety and efficacy study of a sirolimus/cyclosporine regimen for
prevention of acute rejection in recipients of primary mismatched
renal allografts. Transplantation 2001;71:271 -80.
[83] Hoogeveen RC, Ballantyne CM, Pownall HJ, et al. Effect of
sirolimus on the metabolism of apoB100-containing lipoproteins in
renal transplant patients. Transplantation 2001;72:1244-50.
[84] Tur MD, Garrigue V, Vela C, et al. Apolipoprotein CIII is upregulated
by anticalcineurins and rapamycin: implications in transplantation-
induced dyslipidemia. Transplant Proc 2000;32:2783-4.
[85] Morrisett JD, Abdel-Fattah G, Hoogeveen R, et al. Effects of sirolimus
on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal
transplant patients. J Lipid Res 2002;43:1170-80.
[86] Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention
of allograft rejection and vasculopathy in cardiac-transplant recipi-
ents. N Engl J Med 2003;349:847 -58.
[87] Kovarik JM, Hartmann S, Hubert M, et al. Pharmacokinetic and
pharmacodynamic assessments of HMG-CoA reductase inhibitors
when coadministered with everolimus. J Clin Pharmacol 2002;
42:222-8.
[88] Jardine AG, Holdaas H, Fellstrom B, et al. Fluvastatin prevents
cardiac death and myocardial infarction in renal transplant recipients:
post-hoc subgroup analyses of the ALERT Study. Am J Transplant
2004;4:988 -95.
[89] Kahan BD, Podbielski J, Napoli KL, et al. Immunosuppressive
effects and safety of a sirolimus/cyclosporine combination regimen
for renal transplantation. Transplantation 1998;66:1040-6.
[90] Lezaic V, Djukanovic L, Pavlovic-Kentera V. Recombinant human
erythropoietin treatment of anemia in renal transplant patients. Ren
Fail 1995;17:705-14.
[91] Pascual J, Marcen R, Ortuno J. Clinical experience with everolimus
(Certican): optimizing dose and tolerability. Transplantation 2005;
79:S80-4.
[92] Yatscoff RW, Fryer J, Thliveris JA. Comparison of the effect of
rapamycin and FK506 on release of prostacyclin and endothelin in
vitro. Clin Biochem 1993;26:409 -14.
[93] Cahill BC, Somerville KT, Crompton JA, et al. Early experience with
sirolimus in lung transplant recipients with chronic allograft
rejection. J Heart Lung Transplant 2003;22:169 -76.
[94] Kaplan MJ, Ellis CN, Bata-Csorgo Z, et al. Systemic toxicity
following administration of sirolimus (formerly rapamycin) for
psoriasis: association of capillary leak syndrome with apoptosis of
lesional lymphocytes. Arch Dermatol 1999;135:553-7.
[95] Citterlo F, Scata MC, Violi P, et al. Rapid conversion to sirolimus for
chronic progressive deterioration of the renal function in kidney
allograft recipients. Transplant Proc 2003;35:1292-4.[96] Mohaupt MG, Vogt B, Frey FJ. Sirolimus-associated eyelid edema in
kidney transplant recipients. Transplantation 2001;72:162 -4.
[97] Khauli RB, Stoff JS, Lovewell T, et al. Post-transplant lymphoceles:
a critical look into the risk factors, pathophysiology and manage-
ment. J Urol 1993;150:22-6.
[98] Ciancio G, Burke GW, Gaynor JJ, et al. A randomized long-term trial
of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil
versus cyclosporine (Neoral)/sirolimus in renal transplantation. II.
Survival, function, and protocol compliance at 1 year. Transplanta-
tion 2004;77:252-8.
[99] Kandaswamy R, Melancon JK, Dunn T, et al. A prospective rando-
mized trial of steroid-free maintenance regimens in kidney transplant
recipientsan interim analysis. Am J Transplant 2005;5:1529 -36.
[100] Napoli KL, Wang ME, Stepkowski SM, et al. Relative tissue
distributions of cyclosporine and sirolimus after concomitant peroral
administration to the rat: evidence for pharmacokinetic interactions.
Ther Drug Monit 1998;20:123-33.
[101] Podder H, Stepkowski SM, Napoli KL, et al. Pharmacokinetic
interactions augment toxicities of sirolimus/cyclosporine combina-
tions. J Am Soc Nephrol 2001;12:1059-71.
[102] Andoh TF, Lindsley J, Franceschini N, et al. Synergistic effects of
cyclosporine and rapamycin in a chronic nephrotoxicity model.
Transplantation 1996;62:311 -6.
[103] Bonegio R, Lieberthal W. Role of apoptosis in the pathogenesis of
acute renal failure. Curr Opin Nephrol Hypertens 2002;11:301-8.
[104] Keane WF. Proteinuria: its clinical importance and role in
progressive renal disease. Am J Kidney Dis 2000;35:S97-S105.
[105] Morelon E, Kreis H. Sirolimus therapy without calcineurin inhibitors:
Necker Hospital 8-year experience. Transplant Proc 2003;35:52 -7.
[106] Coombes J, Mreich E, Liddle C, Rangan GK. Rapamycin worsens
renal function and intratubular cast formation in protein-overload
nephropathy. Kidney Int 2005;68:2599-607.
[107] Vanrenterghem Y, Ponticelli C, Morales JM, et al. Prevalence and
management of anemia in renal transplant recipients: a European
survey. Am J Transplant 2003;3:835 -45.
[108] Cohen B, Smits JM, Haase B, et al. Expanding the donor pool to
increase renal transplantation. Nephrol Dial Transplant 2005;20:34-41.
[109] Eurotransplant. Eurotransplant Annual Reports 19962003.
www.eurotransplant.nl/?id= annual_report [Last accessed: June
2005].
[110] Morrissey PE, Gohh R, Yango A, et al. Renal tra
Recommended