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

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