Acute rejection incidence

Les traitements
immunosuppresseurs
pour un futur… immédiat.
Henri Kreis
Université Paris V & Hôpital Necker, Paris
DIU Transplantation
Tours, 7-9 janvier 2009
Graft survival at one year
Immunosuppression effect?
100%
50%
1975
1985
1995
2005
Improved short-term graft survival
Post-RT mortality (6 months)
Hôpital Necker 1959 - 2004
Immunosuppression effect?
50
< 1%
1959
1969
1979
1989
Avoiding short term patients’ death
2004
Acute rejection incidence
Acute rejection (%)
Acute rejection
50
45
40
35
30
25
20
15
10
5
0
12-24 months
43.7
6-12 months
36.7
0-6 months
33.9
27.4
22.5
21.4
Meier-Kriesche HU, 2004
Am J Transplant
17.9
15.3
6.1
1995
1996
7.2 6.1
6.75.8
1997
1998
Transplant year
14.6
7.4
5.2
1999
6
2.9
2000
Decreasing the incidence of acute rejection
How does it impacts graft survival?
Causes of late allograft loss
Allograft nephropathy
Death with a functioning graft
M. Pascual,
N Engl J Med 2002
1. L’état des lieux
2. De nouvelles approches
3. Une moindre toxicité
4. La prévention du cancer
5. L’individualisation du traitement
The « 3 signals «
Antibody induction; adult patients
First-time, kidney-only
transplants, age 18 &
older, 1995–2006.
Immunosuppression as
identified to OPTN.
USRDS 2008
Baseline calcineurin inhibitor use;
adult patients
First-time, kidney-only
transplants, age 18 &
older, 1995–2006.
Immunosuppression as
identified to OPTN. CsA:
cyclosporine A; CsM:
cyclosporine
microemulsion.
Tacrolimus includes
traditional & modified
release formulations.
USRDS 2008
Baseline antimetabolite use;
adult patients
First-time, kidney-only
transplants, age 18 &
older, 1995–2006.
Immunosuppression as
identified to OPTN. MMF
includes mycophenolate
mofetil & mycophenolate
sodium.
USRDS 2008
mTOR inhibitor use; adult patients
First-time, kidney-only
transplants, age 18 &
older, 1995–2006.
Immunosuppression as
identified to OPTN.
mTOR: mammalian
target of rapamycin;
includes sirolimus &
everolimus.
USRDS 2008
Steroid use; adult patients
First-time, kidney-only
transplants, age 18 &
older, 1995–2006.
Immunosuppression as
identified to OPTN.
USRDS 2008
Most common immunosuppression regimens at time
of transplant: 2004–2006; adult patients
First-time, kidney-only
transplants, 2003–2005.
Maintenance
immunosuppression as
identified to OPTN. first-time,
kidney-only transplants, age 18
& older, 2004–2006.
Maintenance
immunosuppression as
identified to OPTN. CsA:
cyclosporine A; CsM:
cyclosporine microemulsion.
Cyclo includes CsA & CsM.
MMF: mycophenolate mofetil
& mycophenolate sodium. Tac:
tacrolimus; includes traditional
& modified release
formulations. mTOR:
mammalian target of
rapamycin; includes sirolimus
& everolimus.
USRDS 2008
1. L’état des lieux
2. De nouvelles approches
3. Une moindre toxicité
4. La prévention du cancer
5. L’individualisation du traitement
Nouvelles définitions
du rejet aigu.
C4d -
Médiation
cellulaire
Lymphocyte T
Rejet aigu
Médiation
C4d +
humorale
Lymphocyte B
Ac anti-HLA
+
1. I.V.Igs
2. Anti-CD2O
A multicentre phase III study
is currently
3. Plasma
ongoing
exchanges
with rituximab.
To treat antibody mediated acute
rejection
it is suggested to use one or more of the following treatment
alternatives, with or without corticosteroids: (Weak)
✔ plasma exchange
✔ intravenous immunoglobulin
✔ anti-CD20 antibody
✔ lymphocyte-depleting antibody
Humanized anti-CD3 mabs
• ChAglyCD3 (TRX4): Friend P et al, Transplantation
1999,
• huOKT3gamma1(Ala-Ala), Teplizumab:
Woodle ES et al, Transplantation 1999,
• HuM291, Visilizumab: Norman D et al,
Transplantation 2000,
• NI-0401: fully humanized anti-CD3: a
French trial in acute rejection.
Hill A et al, Br J Haematol 2007
Anti-C5 mabs: indications
• Acute humoral rejection (on going),
• Chronic humoral rejection,
• Recurrence of membranoproliferative
glomerulonephritis (type2),
• Atypical HUS,
• …
Miscellaneous
• Slow release anti-CD25,
• Purine nucleoside phosphorylase
inhibitor,
• Anti-LFA1,
• Anti-CD28,
• Velcade,
• Belimumab,
• ….
PKC θ
AEB071
AEB071
• AEB071: potent and selective inhibitor of
PKCs,
• Several isoforms: classical (α,β), novel
(δ,ε,θ,η) and atypical.
• Isoforms α, β , θ are playing a major role in
T and B cell signaling.
• Safety profile:
A multicentre phase II study
is currently ongoing.
– GI tract,
– Pulse rate,
– Liver.
Slade A et al, A T C 2007
1. L’état des lieux
2. De nouvelles approches
3. Une moindre toxicité
4. La prévention du cancer
5. L’individualisation du traitement
CARMEN study
Tacro + MMF + steroïds versus Anti-IL2r + tacro + MMF
50
% biopsy
proven acute
rejection
Patient and graft survival,
graft function = similar
16.5
16.5
n=278
n=260
Ste +
Ste -
CS Resistant
4.3
5.0
Ste +
Ste -
Rostaing L et al, Transplantation 2005
Calcineurin
inhibitors
=
But !
Nephrotoxicity
Hypertension
CNIs toxicity
Dyslipidemia
New-onset diabetes mellitus
How to decrease CNIs toxicity ?
Minimisation
Conversion
: MMF, mTOR-Is
Avoidance : MMF, mTOR-Is, belatacept…
What have we learned ?
• Early introduction of sirolimus:
•With low dose CNIs: concerns
delayed graft function (incidence,
length) ?
guidelines ?
Increased CNIs nephrotoxicity?
•Without CNIs: concerns
acute rejection rate (++ with low dose
siro),
healing complications,
high drop out rate.
What have we learned ?
• Secondary introduction of sirolimus:
•When?
Not too early: same as early introduction,
Not too late: little benefit with regard to
function,
Between 3 months and one year?
•To increase efficacy and safety:
Patients with GFR > 40ml/min and low
proteinuria,
Better ? Biopsy, pharmacogenetics…
The driving force: prevention of cancer!
CNI avoidance: belatacept
ISA247
MR4
CsA analog : ISATX247
• CsA analog ISATX247: 3 times more
potent than CsA and similar toxicity
in vitro.
• Phase IIb: IS247 versus tacro:
– Preliminary results at 3 months,
– Acute rejection = similar,
– Renal function = similar,
– Safety: less diabetes and tremor.
Busque S et al, A T C 2007
Extended release tacrolimus
• Tacro (MR4): non inferiority at one
year compared to Tac and Csa (+ CsMMF) (Silva HT et al, Am J Transplant 2007).
• After 2 year follow-up:
Acute rejection: 12.5 vs 10.4 vs 16.0,
Patient and graft survival similar,
Safety profile: no clear benefit / tacro
Diabetes: 16.4 vs 11.8 vs 7.1. Yang H et al, A T C 2007
1. L’état des lieux
2. De nouvelles approches
3. Une moindre toxicité
4. La prévention du cancer
5. L’individualisation du traitement
Nantes experience
Dantal J et al, Lancet 1998
Prospective study « low dose » CsA (75125ng/ml) versus « normal dose » CsA (150250ng/ml).
Results:
Cancer: 23 versus 37 after 66 months follow-up,
Acute rejection: 9 versus 1.
STUDY DESIGN 316
Inclusion
• 0.5 to 10 yrs after renal tx
• CsA or TAC
• MMF or AZA
• Steroids
2:1 Randomization (N = 830)
SRL Conversion (n = 555)
• SRL troughs: 8-20 ng/mL
(by chromatographic method)
CNI Continuation (n = 275)
•Continue CsA or TAC
(can switch CsA ⇔ TAC)
• MMF or AZA: Continue or stop
•MMF or AZA: Continue or stop
• Continue Steroids
•Continue Steroids
Incidence of malignancy
1. L’état des lieux
2. De nouvelles approches
3. Une moindre toxicité
4. La prévention du cancer
5. L’individualisation du traitement
Individualizing immunosuppression
. Immunological risk:
- first or subsequent transplantation,
- anti-HLA immunization,
- positive historical cross-match…
. Cardiovascular risk profile,
. Risk of post-transplant diabetes mellitus,
. Risk of delayed graft function,
. Living related versus deceased donor,
. Etc…
What makes him different ?
General pathways of metabolism
veina.
porta
Systemic circulation
Intestinal
lumen
Intestinal
wall
Liver
CYP3A
P-gp
feces
Intestinal metabolism
CYP3A
P-gp
Hepatic first-pass
D. Anglicheau et al, JASN 2003
Tacrolimus and CYP3A5*3 genetic polymorphism
P=0.01, Kruskall Wallis
0.02
0.02
ns
.35
< 0.05
180
ns
.30
.25
.20
.15
.10
Concentration / Dose ratio
Tacrolimus Daily Dose (mg/kg/d)
P<0.03, Kruskall Wallis
ns
160
140
120
100
80
60
40
20
.05
*1/*1
(n = 4)
*1/*3
(n = 9)
*3/*3
(n = 67)
0
*1/*1
(n = 4)
*1/*3
(n = 9)
*3/*3
(n = 67)
Patients with the CYP3A5*1 allele (i.e. CYP3A5 expressors) require more
tacrolimus to reach target predose concentrations compared with CYP3A5*3/*3
genotype (i.e. CYP3A5 non-expressors).
Thervet at al. Transplantation 2003:1233.
Pour Conclure
CNI avoidance: OKT3
90
OKT3
80
70
60
50
Steroids (H or L)
Debure A et al, Transplantation 1988
Meier-Kriesche HU,
2004 Am J Transplant
1995
1988
Very modest improvements !
Long term graft survival of kidney transplants in past 20 years
Percent Graft Survival
100
90
1987-1995
1996-2006
1987-1995
1996-2006
100
90
80
80
70
70
60
60
50
50
40
30
20
10
0
HLA-Id Sib
Spouse
Parent
Cadaver
0 1 2 3 4 5 6 7 8 9 10
1996
2006
40
3587
801
5081
60035
5412
6568
8112
89894
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10
Years Posttransplant
Kaneku HK et al, Clinical Transplants 2006
CsA
Peri-Operative Antibiotics
Cohen J, et al.J Hosp Infect. 1988,11:357-63.
Platt R. Rev Infect Dis. 1984,6 Suppl 4:S880-6.
Keighley MR. Br Med J. 1983, 286:1844-6.
Kasiske BL, et al. Urol Clin North Am. 1983,10:35-50.
Kissel SM, et al. N Y State J Med. 1982,82:1543-5.
Shapiro M. Infect Control. 1982, 3:38-40.
Townsend TR, et al. Infect Control. 1980,1:93-6.
Polk HC Jr, et al.JAMA. 1980 Sep 19;244:1353-4.
Hurley DL, et al. Surg Clin North Am. 1979,59:919-33.
Barber MS, et al. Surgery. 1979,86:23-9.
Phelan JP, et al. Am J Obstet Gynecol. 1979,133:474-8.
Prophylactic Anti-CMV Agent
Erice A, Jordan MC, Chace BA, Fletcher C, Chinnock BJ, Balfour
HH Jr.
Ganciclovir treatment of cytomegalovirus disease in transplant
recipients and
other immunocompromised hosts.
JAMA. 1987,257:3082-7.
Pettersson E, Hovi T, Ahonen J, Fiddian AP, Salmela K,
Hockerstedt K,
Eklund B, von Willebrand E, Hayry P.
Prophylactic oral acyclovir after renal transplantation.
Transplantation. 1985,39:279-81.
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Merci de votre
attention!
…que celui qui ne veut pas entendre
DIU Transplantation
Tours, 7-9 janvier 2009