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 50 Immunosuppression effect? < 1% 1959 1969 1979 1989 Avoiding short term patients death 2004
Acute rejection incidence Acute rejection (%) 50 45 40 35 30 25 20 15 10 5 0 36.7 22.5 21.4 43.7 33.9 27.4 17.9 15.3 14.6 6.1 7.26.1 6.7 7.4 5.8 5.2 Acute rejection 12-24 months 6-12 months 0-6 months Meier-Kriesche HU, 2004 Am J Transplant 1995 1996 1997 1998 1999 2000 Transplant year Decreasing the incidence of acute rejection How does it impacts graft survival? 6 2.9
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 USRDS 2008 First-time, kidney-only transplants, age 18 & older, 1995 2006. Immunosuppression as identified to OPTN.
Baseline calcineurin inhibitor use; adult patients USRDS 2008 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.
Baseline antimetabolite use; adult patients USRDS 2008 First-time, kidney-only transplants, age 18 & older, 1995 2006. Immunosuppression as identified to OPTN. MMF includes mycophenolate mofetil & mycophenolate sodium.
mtor inhibitor use; adult patients USRDS 2008 First-time, kidney-only transplants, age 18 & older, 1995 2006. Immunosuppression as identified to OPTN. mtor: mammalian target of rapamycin; includes sirolimus & everolimus.
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 USRDS 2008 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.
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 C4d + Médiation humorale Lymphocyte B Ac anti-hla +
1. I.V.Igs 2. Anti-CD2O A multicentre phase III study 3. Plasma is currently ongoing with rituximab. exchanges
it is suggested to use one or more of the following treatment alternatives, with or without corticosteroids: (Weak) plasma exchange To treat antibody mediated acute intravenous immunoglobulin anti-cd20 antibody rejection 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 is and currently B cell signaling. ongoing. Safety profile: GI tract, Pulse rate, Liver. A multicentre phase II study 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 Patient and graft survival, graft function = similar % biopsy proven acute rejection 16.5 n=278 16.5 n=260 CS Resistant 4.3 5.0 Ste + Ste - 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 (+ Cs- MMF) (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 (75-125ng/ml) versus «normal dose» CsA (150-250ng/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) MMF or AZA: Continue or stop Continue Steroids CNI Continuation (n = 275) Continue CsA or TAC (can switch CsA TAC) MMF or AZA: Continue or stop 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 CYP3A P-gp feces Intestinal metabolism Hepatic first-pass
D. Anglicheau et al, JASN 2003
Tacrolimus and CYP3A5*3 genetic polymorphism P<0.03, Kruskall Wallis P=0.01, Kruskall Wallis 0.02 0.02 Tacrolimus Daily Dose (mg/kg/d).35.30.25.20.15.10 ns ns Concentration / Dose ratio 180 160 140 120 100 80 60 40 20 ns < 0.05.05 *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 80 70 60 50 OKT3 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 80 70 60 50 40 30 20 10 0 1987-1995 1996-2006 1996 2006 40 HLA-Id Sib 3587 5412 30 Spouse 801 6568 20 Parent 5081 8112 10 Cadaver 60035 89894 0 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years Posttransplant 100 90 80 70 60 50 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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