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An
ti-c
alc
ine
urí
nic
os n
o
Jo
sep
M G
rin
yó
Ho
sp
ital
Un
ivers
itari
de B
ell
vit
ge.
IDIB
EL
LU
niv
ers
itat
de
Barc
elo
na
Calc
ine
urin I
nhib
itors
: M
ech
an
ism
of
Actio
n
CsA
: C
yclo
spo
rine
FK
506
: T
acro
limu
s
FK
BP
: F
K B
ind
ing
Pro
tein
Cp
N:
Cyclo
phili
n
NF
-AT
: N
ucle
ar
Fa
cto
r o
f
Activa
ted
T-c
ells
(c-
cyto
solic
co
mpo
nen
t; n
-
nu
cle
ar
co
mp
on
en
t).
Stepkowski, Expert Rev
Mol Med, 2000;2(4):1
CA
LC
INE
UR
IN I
NH
IBIT
OR
S
Aff
ere
nt
arte
riole of
glom
erulus
withou
t CsA
or
FK
AA with
CyA
or FK
prese
nt
CN
I T
oxic
ity S
co
rin
g
His
tolo
gic
al
featu
reC
rite
ria
Sco
re
% G
lom
eru
loscle
rosis
0; 1-2
5%
, 2
6-5
0%
; >
50
%0
-3
Me
sa
ng
ial m
atr
ix e
xp
ansio
n0
; 1-2
5%
, 2
6-5
0%
; >
50
%0
-3
Isom
etr
ic tu
bu
lar
vacu
oliz
atio
n0
; 1-2
5%
, 2
6-5
0%
; >
50
%0
-3
Tu
bu
lar
atr
oph
y0
; 1-2
5%
, 2
6-5
0%
; >
50
%0
-3
Inte
rstitia
l fib
rosis
0-5
%; 6-2
5%
, 2
6-5
0%
; >
50%
0-3
Art
eri
ola
r h
yalin
e0
; m
ild-m
ode
rate
(1
art
eri
ole
);
mo
dera
te-s
eve
re (
1-2
art
erio
le);
se
vere
(m
an
y a
rteri
ole
s)
0-3
To
tal score
18
Exp
eri
men
tal
nep
hro
toxic
ity
ED
1
alf
a-S
MA
Ch
ron
ic R
en
al F
ailu
re a
fte
r T
ran
sp
lan
tati
on
of
a N
on
ren
al O
rga
n
Ojo A, et al.NEJM
349:931-940, 2003.
70%
50%
20%
10
-15
%
Incid
ence o
f acute
reje
ction
Imm
ure
l-P
D
Sandim
mun/P
rogra
f-P
D
Sandim
mun/P
rogra
f-P
D
CellC
ept
Sadim
mu
n/P
rogra
f
Rapam
une
Help
Me
ta-a
na
lysi
s o
n C
NI
spa
rin
g
wit
h M
MF
in
KT
x:
Re
na
l fu
nct
ion
Mo
ore
J …
…B
orr
ow
s R
, T
ran
spla
nta
tio
n 2
00
9;
87
: 5
91
-60
5.
Me
ta-a
na
lysi
s o
n C
NI
spa
rin
g
wit
h M
MF
in
KT
x:
Mo
rta
lity
Mo
ore
J …
…B
orr
ow
s R
, T
ran
spla
nta
tio
n 2
00
9;
87
: 5
91
-60
5.
Me
ta-a
na
lysi
s o
n C
NI
spa
rin
g
wit
h M
MF
in
KT
x:
Inci
de
nce
of
gra
ft l
oss
Mo
ore
J …
…B
orr
ow
s R
, T
ran
spla
nta
tio
n 2
00
9;
87
: 5
91
-60
5.
Renal function
Abramowicz et al JA
SN 2005; 16:2234-40
Reje
ction E
pis
odes
Abramowicz et al JA
SN 2005; 16:2234-40
Graft loss-CR
n=9
n=3
CNI withdrawal from sirolimus immunosuppression
(absolute risk difference of acute rejection)
Mulay et al. AJT 2005; 5: 1748.
CNI withdrawal from sirolimus immunosuppression
(RR of graft loss)
Mulay et al. AJT 2005; 5: 1748.
Cre
ati
nin
e c
lea
ran
ce
Mulay et al. AJT 2005; 5: 1748.
Eff
ica
cy a
nd
sa
fety
of
an
eve
roli
mu
s/e
nte
ric-
coa
ted
my
cop
he
no
late
so
diu
m
reg
ime
n a
fte
r ca
lcin
eu
rin
in
hib
ito
r w
ith
dra
wa
l
in t
he
no
vo
re
na
l tr
an
spla
nt
reci
pie
nts
:
Re
sult
s o
f th
e Z
eu
s tr
ial
Bu
dd
e e
t a
l. L
an
cet
20
11
.
The Z
eus trial: a
cute
reje
ction
Bu
dd
e e
t a
l. L
an
cet
20
11
.
The Z
eus trial: R
enal fu
nction
Bu
dd
e e
t a
l. L
an
cet
20
11
.
BE
NE
FIT
an
d B
en
efit-
EX
T S
tud
y D
esig
ns. P
ha
se
III
LI =
le
ss i
nte
nsi
ve
; M
I =
mo
re i
nte
nsi
ve
.
Ra
nd
om
iza
tio
n
Pri
ma
ry c
lin
ica
l e
nd
po
ints
10
mg
/kg
14
28
42
56
70
84
11
21
40
16
8D
AY
15
5 m
g/k
g e
ve
ry 4
we
eks
Cycl
osp
ori
ne
*
n =
22
1
Be
lata
cep
t M
I*
n =
21
9
Be
lata
cep
t LI
*
n =
22
6
10
mg
/kg
5 m
g/k
g e
ve
ry 4
we
eks
14
28
56
84
11
2D
AY
15
15
0–
25
0 n
g/m
l
28
DA
Y 11
50
–3
00
n
g/m
l
36
month
s
24
month
s
12
month
s
6
month
s
*A
ll p
ati
en
ts r
ece
ive
d b
asi
lixi
ma
b i
nd
uct
ion
, m
yco
ph
en
ola
te m
ofe
til,
an
d c
ort
ico
ste
roid
s
Be
lata
cep
t in
re
na
l tr
an
spla
nta
tio
n
Vin
centi e
t al. A
m J
Tra
nspl 2010;
10:
53
5-4
6.
Durr
bach e
t al. A
m J
Tra
nspl 2010
; 10:
547-5
7
Bela
tacept P
hase 3
Clin
ical T
rial R
esults:
Measure
d a
nd C
alc
ula
ted G
FR
P<
0.0
001
P<
0.0
001
P<
0.0
001
P<
0.0
001
P=
0.0
08 P=
0.1
0
P<
0.0
1
P<
0.0
1
22
Be
lata
ce
pt P
ha
se
3 C
linic
al T
ria
l
Re
su
lts:
Incid
ence
of A
cu
te R
eje
ction
Vin
cen
ti F
et
al
Am
J T
ran
spla
nt
20
09
; 9
(Su
pp
l 2
):1
91
; A
bst
ract
#4
Du
rrb
ach
A e
t a
l A
m J
Tra
nsp
lan
t 2
00
9;
9(S
up
pl
2):
19
9;
Ab
stra
ct #
27
Ba
nff
Gra
de
Mil
d a
cu
te (
IA)
7(3
)4
(2)
3(1
)M
ild
ac
ute
(IB
)3
(1)
8(4
)5
(2)
Mo
de
rate
ac
ute
(I
IA)
17
(8)
16
(7)
6(3
)
Mo
de
rate
ac
ute
(I
IB)
20
(9)
10
(4)
2(1
)
Se
ve
re A
cu
te (
III)
2(1
)1
(<1
)0
IA0
4(2
)2
(1)
IB7
(4)
2(1
)2
(1)
IIA
10
(5)
17
(10
)17
(9)
IIB
16
(9)
8(5
)5
(3)
III
00
0
Bo
th b
ela
tacep
t g
rou
ps m
et
20
% N
I m
arg
in v
s. C
sA
* D
id n
ot
meet
20%
NI
marg
in^
Met
20
% N
I m
arg
in
23
BE
NE
FIT
BE
NE
FIT
-EX
T
Be
lata
ce
pt
Ph
ase
3 C
linic
al T
ria
l R
esu
lts:
Re
na
l
Fu
nctio
n M
ain
tain
ed
in
Pa
tie
nts
with
Acu
te R
eje
ctio
n
n=
149 n
=37
n=
171 n
=13
n=
165 n
=25
Be
lata
cep
t P
ha
se 3
Cli
nic
al
Tri
al
Re
sult
s:
Re
du
ced
Pre
va
len
ce o
f C
hro
nic
All
og
raft
Ne
ph
rop
ath
y
P=
0.0
58
P=
0.0
01
P=
0.2
289
Criticis
ms t
o C
NI
sparin
g/a
void
ance s
trate
gie
s
•W
ithout fu
lly r
ational basis
.
•M
issin
g M
OA
s d
iffe
rences o
f IS
•H
iera
rchy, tim
ing?
•Lack o
f assessm
ent of T
and B
cell
responses.
•C
orr
ela
tion b
etw
een im
mune r
esponses
and g
raft d
am
age/function?
•B
iom
ark
ers
•In
dis
crim
inate
str
ate
gie
s
0
20
40
60
80
100
120
140
160
180
200
Dir
ect
Path
wa
y(d
on
or-
sp
ecif
ic)
300
350
400
Dir
ect
Path
wa
y(T
hir
d P
art
y)
Ind
irect
Path
wa
y(d
on
or-
sp
ecif
ic)
Ind
irect
Path
wa
y(T
hir
d P
art
y)
Elispots / 300,000 PBMC
p =
0.0
01
61.2
± ±±±9.6
20 ± ±±±
21
82 ± ±±±
85
14.3
± ±±±20
59
% p
os
6
0%
pos
Dir
ect
pa
thw
ay 3
tim
es h
igh
er
tha
n in
dir
ect
resp
on
se
s
Dir
ect
pa
thw
ay 3
tim
es h
igh
er
tha
n in
dir
ect
resp
on
se
s
an
d in
cre
ase
d c
om
pa
red
to
ea
rly p
ost
an
d in
cre
ase
d c
om
pa
red
to
ea
rly p
ost --
Tx
Tx
Besta
rd e
t al.J A
m S
oc N
ephro
l, 2
008; 19: 1419-2
9
NO
(n=
19)
YE
S
(n=
15)
Pro
tein
uri
a
20
40
60
80
Indirect Elispots / 300,000 PBMC
*
p =
0.0
22
Indirect
path
way T
-cell
allo
resp
on
se is r
ela
ted t
o
pro
tein
uri
a a
nd t
ime a
fter
transp
lanta
tion
12
24
36
48
60
72
84
96
108
120
132
Tim
e a
fter
tran
sp
lan
tati
on
(m
on
ths)
0102
0
40
60
Indirect Elispots / 300,000 PBMC�
�
��
�
�
�
� �
�
�
�
�
�
�
� �
�
�
�
�
�
�
�
�
� ��
�
�
�
�
�
80
r =
0.3
51,
p =
0.0
45
Only
one o
ut of 33 s
cre
ened p
atients
had c
ircula
ting D
SA
after
Only
one o
ut of 33 s
cre
ened p
atients
had c
ircula
ting D
SA
after
transpla
nta
tion. T
his
patient had a
positiv
e indirect but a n
ega
transpla
nta
tion. T
his
patient had a
positiv
e indirect but a n
ega
tive d
irect
tive d
irect
path
way E
lispot
path
way E
lispot B
esta
rd e
t al.J A
m S
oc N
ephro
l, 2
008; 19: 1419-2
9
In v
itro
evalu
ation im
mun
osup
pre
ssiv
ion o
n c
ircula
ting m
em
ory
/eff
ecto
r T
cells
Be
sta
rd O
et
al T
ran
spl In
t 2011
6-M
on
th E
LIS
PO
T (
N=
61
)
21
%
71
%
8%
N/A
NE
G
PO
S
PR
E-T
X E
LIS
PO
T (
N=
64
)
61
%
34
%
5%
N/A
NE
G
PO
S
6-M
on
th E
LIS
PO
T c
ha
ng
es
(N
=6
1)
8%
48
%
13
%
8%
23
%
NE
G--
>N
EG
NE
G--
>P
OS
PO
S--
>P
OS
PO
S--
>N
EG
N/A
Dis
trib
ution o
f d-s
celu
llar
imm
une r
esp
onse
(N=
3)
(N=
22)
(N=
39)
(N=
5)
(N=
13)
(N=
3)
(N=
43)
6-M
donor-
specific
Elis
pot
chang
es a
nd
Gra
ft function e
vo
lutio
nS
eru
m C
rea
tin
ine
(um
ol/L
)
eG
FR
(m
l/m
in)
*
**
*
SR
LS
RL
SR
LS
RL
TA
CT
AC
TA
CT
AC
SR
LS
RL
SR
LS
RL
TA
CT
AC
TA
CT
AC
De
no
vo
re
na
l T
x
Th
ym
og
lob
uli
n +
Ta
cro
lim
us+
MM
F
Th
ym
og
lob
uli
n +
Be
lata
cep
t +
MM
F
Th
ym
og
lob
uli
n +
Be
lata
cep
t +
Sir
oli
mu
s
Be
lata
cep
t-b
ase
d C
NI
an
d s
tero
id-f
ree
re
gim
en
(exp
lora
tory
ph
ase
IIA
tri
al)
1 m
on
th3
mo
nth
s6
mo
nth
s
12
mo
nth
s
Pri
ma
ry c
lin
ica
l e
nd
po
int
All
pa
tie
nts
re
ceiv
ed
th
ym
og
lob
uli
n (
1.5
mg
/kg
iv
on
Da
ys
1–
4 t
o m
ax
to
tal
do
se o
f 6
mg
/kg
)
All
pa
tie
nts
re
ceiv
ed
iv
ste
roid
s o
n D
ay
s 1
(5
00
mg
), 2
(2
50
mg
), 3
(1
25
mg
) a
nd
4 (
60
mg
)
Be
lata
cep
t: M
I re
gim
en
Co
nv
en
tio
na
l le
ve
ls o
f T
ac
an
d S
RL
Ferg
uson,
Grin
yo e
t al.
Am
J T
ranspla
nt.
2011;1
1:6
6-7
6
Acu
te R
eje
ctio
n b
y M
on
th 6
Ban
ff g
rad
e, n
(%
)B
an
ff g
rad
e, n
(%
)B
ela
tacep
tB
ela
tacep
t+
MM
F+
MM
FB
ela
tacep
tB
ela
tacep
t+
SR
L+
SR
LT
AC
TA
C+
MM
F
+ M
MF
Mil
d a
cu
te (
IA)
Mil
d a
cu
te (
IA)
Mil
d a
cu
te (
IB)
Mil
d a
cu
te (
IB)
Mo
de
rate
ac
ute
(II
A)
Mo
de
rate
ac
ute
(II
A)
Mo
de
rate
ac
ute
(II
B)
Mo
de
rate
ac
ute
(II
B)
Se
ve
re a
cu
te (
III)
Se
ve
re a
cu
te (
III)
00 00
2 (
6)
2 (
6)
1 (
3)
1 (
3)
1 (
3)
1 (
3)
00 00 00
1 (
4)
1 (
4)
00
00 00
1 (
3)
1 (
3)
00 00
Ferg
uson,
Grin
yo e
t al.
Am
J T
ranspla
nt.
2011;1
1:6
6-7
6
35
Mean C
alc
ula
ted G
FR
(M
DR
D F
orm
ula
) O
ver
Tim
e
Ferg
uson,
Grin
yo e
t al.
Am
J T
ranspla
nt.
2011;1
1:6
6-7
6
An
ti-d
on
or
sup
pre
ssiv
e a
ctivity o
f T
regs
from
diffe
ren
t IS
re
gim
ens in
allo
ge
ne
ics c
o-c
ultu
re a
t d
iffe
ren
t tim
e-p
oin
ts.
Besta
rd e
t al. T
ranspla
nt
Int
2011.