Post on 11-Apr-2015
Papel de los anticalcineurínicos en la historia del trasplante renal
Josep M. GrinyóHospital Universitari de Bellvitge
Universitat de Barcelona
Inmunosupresión convencional
AZA-CS
Inicios del trasplante hasta mediados 80
Jean-François Borelpropiedades inmunossupressorasde la ciclosporina (1972)
Calne RY, Roller K, White DJG, et al. “Cyclosporin A initially as the only immunosuppressant in 34recipients of cadaveric organs: 32 kidneys, 2 pancreas and 2 livers “Lancet 1979; 2: 1033-1036.
Beneficios de CsA en trasplante renal en comparación con la IS convencional
(mediados 80)
• Reducción de rechazo agudo
• Reducción dosis acumulativas de esteroides
• Reducción de infección bacteriana
• Introducción de la monitorización PK en
trasplante
• Aumento de la supervivencia a 1 año.
100%
50%
Good 80%
Moderate 50%
Poor 35%
Inmunosupresión convencional ( AZA+ Esteroides)
CsA
Efecto centro atenuado por la CsA (EDTA)
SI 1 año
Graft failure and patient’s death in the first year after transplantation 1984-2002
1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Transplant year
0
5
10
15
20
25
30Percentatge
Graft failure Death
RMR Catalunya
Cyclosporine vs azathioprine in renal transplantation
CsA AZA p
Acute rejection 39.1% 71.8% .018
MPN boluses 6+7.3 11.6+10 .000
DGF 44.5% 30.8% .018
Duration DGF (days) 19.9+12.2 13.5+6.3 .000
Marcen et al. Transplantation 2001; 72: 57
ALG, low-dose CsA vs conventional CsA doses(n= 100)
ALG-CsA CsA p
Acute rejection (3 m) 18% 40% .01
DGF 16% 16% ns
Duration DGF (days) 3.3+2 16.2+10.7 <.05
Grinyo et al. Transplantation 1990; 49: 1114-7
Causes of graft loss
CsA AZA p
Acute rejection 10.9% 23.8% .046
Primary nonfunction 4.7% 4.9% .27
CAN 40.6% 16.8% .008
DFG 26.6% 34.6% .24
Other 17.1% 19.8% ns
Marcen et al. Transplantation 2001; 72: 57
(P <0.025).
First cadaveric graft survival
Marcen et al.Transplantation 2001; 72: 57
First cadaveric graft survival after 1 year in patients on CsA and Aza therapies
Marcen et al.Transplantation 2001; 72: 57
90868278740
10
20
30
40
50
60
70
80
90
100
1
10
1-y GS %Half-life y (>1y)
Year of Transplant (1975-1990)
1-y
GS
%
Hal
f-li
fe y
(>
1y)
Evolution of 1-y GS and allograft half-lifeEvolution of 1-y GS and allograft half-life
Gjertson 91.Gjertson 91.
0
5
10
15
20
25
30
35
40
1988 1989 1990 1991 1992 1993 1994 1995
CadavericLiving
Renal allograft half-lifeDeath censored
Hariharan, NEJM 2000Hariharan, NEJM 2000
N=98 340 pacientesN=98 340 pacientes
Long term results of solid organ transplantation
CTS 2004.
Inconvenientes de los anticalcineurínicos en Tx renal
• Nefrotoxicidad
• Aumento de factores de riesgo cardiovascular
• Otros
Optimising immunosuppressive regimens to minimise CVD risk
Hyperlipidaemia Hypertension
Diabetes mellitus
Tacrolimus – + ++
Ciclosporin microemulsion ++ ++ ++
Corticosteroids ++ ++ +++
Sirolimus +++ – –
Mycophenolate mofetil – – –
Monoclonal antibodies – – – – = none; + = slight; ++ = moderate; +++ = severe
Semiquantitative estimation of effects of immunosuppressants on cardiovascular risk factors
Adapted from Fellström B. BioDrugs 2001;15:261–78
Post-transplant blood pressure is a predictor of long-term graft survival
Reproduced from Opelz G, et al. Kidney Int 1998;53:217–22
< 120120-129130-139140-149150-159160-169170-179
≥ 180
N=2805N=4488N=5961N=6670N=4443N=2925N=1217
N=1242
Time (years)
0 1 2 3 4 5 6 7
100
90
80
70
60
50
0
One-year systolic blood pressure (mmHg)
Fu
nct
ion
al g
raft
s su
rviv
ing
(%
)
25–34 35–44 45–54 55–64 65–74 75–84
Cardiovascular mortality in renal transplant recipients
10
1
0.1
0.01
0.001
An
nu
al m
ort
alit
y (%
)
Age (years)
Renal transplant recipientsGeneral population
Reproduced from Foley RN, et al. Am J Kidney Dis 1998;32(Suppl. 3):112–19
Retos de los anticalcineurínicos
• Edad avanzada del donante y receptor
– Mayor susceptibilidad a la NTX
– Agravar función renal
– Empeorar el perfil de riesgo cardiovascular
– Limitar la potencial mejora de los resultados?
Chronic Renal Failure in Nonrenal Transplants
Ojo AO et al. NEJM, 2003
• 69,321 US nonrenal transplants (1990-2000)
• CRF defined as GFR < 29 ml/min/1.73m2
Proportion of Deceased Donor Transplants with Donor Age > 55
years: 1988 –2003
0
5
10
15
20 268% %
Transplant Year Vasudev et al, ATC 2005, Abstract # 1001
Long-term Kidney Transplant Survival Deceased Donor Transplants: 1988 – 2003
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
1988198919901991199219931994199519961997199819992000200120022003
N =121,610
Post-transplant YearsVasudev et al, ATC 2005, Abstract # 1001
Donor age and renal functionDonor age and renal function
RMRC (informe estadístic 1999)RMRC (informe estadístic 1999)
Creatinine clearance at 3 yearsCreatinine clearance at 3 years
< 20 20-29 30-39 40-49 50-59 60-69 > 690 %
20 %
40 %
60 %
80 %
100 %
> 59 ml/min> 59 ml/min
30-59 ml/min30-59 ml/min
< 30 ml/min< 30 ml/min
dialysisdialysis
deaddead
Donor age (years)Donor age (years)
Cadaveric Renal Transplant Survival
0
5
10
15
20
25
1988 1989 1990 1991 1992 1993 1994 1995 1996 1997
Gra
ft H
alf
-Lif
e (
ye
ars
)
All Cads Creat <= 1.5 Creat > 1.5
Hariharan et al. Kidney Int: 62:311-18, 2002
Overall 42%
SCr <1.5mg/dL: 74%
SCr >1.5mg/dL: 21%
7.9
10.9
6.2
11.2
19.0
7.5
2.6-4.0 2.2-2.5 1.9-2.1 1.7-1.8 1.5-1.6 1.3-1.4 <1.3
0
0.5
1.0
1.5
2.0
2.5
3.0
2.26*
1.67*1.49*
1.37*1.19*
1.03 1.00
Renal dysfunction is a strong risk factor for cardiovascular death
*p<0.05
RR
Serum creatinine (mg/dL)
CV death with a functioning graft
Adapted from Meier-Kriesche HU, et al. Transplantation 2003;75:1291–5
Significant Improvement In Estimated Long-term
Survival Only Among Donors < 55 years
Multivariate analyses adjusted for the same donor, recipient andtransplant related factors
Gill J et al. Kidney International 2005 (in press)
Kasiske et al,AJT 2005(in press)
All Transplants
Transplants withFunctioning GraftAt 3 months
Transplants withFunctioning GraftAt 12 months
Long-term Kidney Transplant Survival
• Steady Improvements in long-term survival
in recent years.
• Steady Improvements in graft survival
when estimated from 3 or 12 months post-
transplant.
Kasiske B. et al, AJT 2005 (in press)
Factores que pueden influir en los resultados del trasplante renal a largo plazo
• Calidad del órgano (edad donante, ECD)
• Alorreactividad ( HLA, sensibilización,
inmunosupresión, rechazo agudo y crónico (NCT)
• Estado del paciente (enfermedades asociadas,
comorbilidad)
2000
2001
2002
1999
1998
1997
Maintenance Therapy at Baseline – First Solitary Transplants 1995-2002
Year of Transplant
Rel
ativ
e F
requ
ency
1995
19961997
1998
FK /MMF
CSA /MMF
CSA /RAPA
FK /RAPA
FKOnly
CSAOnly
RAPA /MMF
01020304050607080
0
10
20
30
40
50
60
70
80
0.7
45.7
24.0
5.26.03.23.42.5
1996
Maintenance Therapies** Other regiments not displayed
Rel
ativ
e F
requ
ency
ICN
imTOR
MPA
Acm anti-IL2R
Ac policlonales
Jak3i ?
LEA
FK778
ICNICNMMFMMF
AZAAZA
imTORimTOR
60s60s80s80s
mmeed 90sd 90s20002000
Introducción de xenobióticos en trasplante de órganos
CNICNIMMFMMF
AZAAZAimTORimTOR
60s60s80s80s
mmeed 90sd 90s20002000
??
Uso transitorio de ICN?Uso transitorio de ICN?
Introducción de xenobióticos en trasplante de órganos
ICN en trasplante renal
• Serendipity
• El azar y la necesidad (Monod)
• Identificar grandes éxitos detrás de
pequeños fracasos
NFAT
ILs
ICN ?
Inhibición de la activación célula T en IS