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Papel de los anticalcineurínicos en la historia del trasplante renal

Papel de los anticalcineurínicos en la historia del trasplante renal. Josep M. Grinyó Hospital Universitari de Bellvitge Universitat de Barcelona. Inmunosupresión convencional AZA-CS. Inicios del trasplante hasta mediados 80. Jean-François Borel propiedades inmunossupressoras

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Papel de los anticalcineurínicos en la historia del trasplante renal

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  1. Papel de los anticalcineurínicos en la historia del trasplante renal Josep M. Grinyó Hospital Universitari de Bellvitge Universitat de Barcelona

  2. Inmunosupresión convencional AZA-CS Inicios del trasplante hasta mediados 80

  3. Jean-François Borel propiedades inmunossupressoras de la ciclosporina (1972)

  4. Calne RY, Roller K, White DJG, et al. “Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreas and 2 livers “ Lancet 1979; 2: 1033-1036.

  5. 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.

  6. Inmunosupresión convencional ( AZA+ Esteroides) SI 1 año 100% Good 80% Moderate 50% CsA 50% Poor 35% Efecto centro atenuado por la CsA (EDTA)

  7. Percentatge 30 25 20 15 10 5 0 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Transplant year Graft failure Death Graft failure and patient’s death in the first year after transplantation 1984-2002 RMR Catalunya

  8. 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

  9. 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

  10. 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

  11. First cadaveric graft survival (P <0.025). Marcen et al.Transplantation 2001; 72: 57

  12. First cadaveric graft survival after 1 year in patients on CsA and Aza therapies Marcen et al.Transplantation 2001; 72: 57

  13. 100 10 90 80 70 60 50 40 1-y GS % 30 Half-life y (>1y) 20 10 0 1 74 78 82 86 90 Evolution of 1-y GS and allograft half-life Half-life y (>1y) 1-y GS % Year of Transplant (1975-1990) Gjertson 91.

  14. Renal allograft half-lifeDeath censored N=98 340 pacientes Hariharan, NEJM 2000

  15. Long term results of solid organ transplantation CTS 2004.

  16. Inconvenientes de los anticalcineurínicos en Tx renal • Nefrotoxicidad • Aumento de factores de riesgo cardiovascular • Otros

  17. Optimising immunosuppressive regimens to minimise CVD risk Semiquantitative estimation of effects of immunosuppressants on cardiovascular risk factors – = none; + = slight; ++ = moderate; +++ = severe Adapted from Fellström B. BioDrugs 2001;15:261–78

  18. 100 90 < 120 N=2805 120-129 N=4488 80 130-139 N=5961 140-149 N=6670 150-159 N=4443 70 160-169 N=2925 170-179 N=1217 60 ≥ 180 N=1242 50 0 Post-transplant blood pressure is a predictor of long-term graft survival One-year systolic blood pressure (mmHg) Functional grafts surviving (%) 0 1 2 3 4 5 6 7 Time (years) Reproduced from Opelz G, et al. Kidney Int 1998;53:217–22

  19. Cardiovascular mortality in renal transplant recipients 10 1 0.1 0.01 0.001 Annual mortality (%) Renal transplant recipients General population 25–34 35–44 45–54 55–64 65–74 75–84 Age (years) Reproduced from Foley RN, et al. Am J Kidney Dis1998;32(Suppl. 3):112–19

  20. 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?

  21. Chronic Renal Failure in Nonrenal Transplants • 69,321 US nonrenal transplants (1990-2000) • CRF defined as GFR < 29 ml/min/1.73m2 Ojo AO et al. NEJM, 2003

  22. Proportion of Deceased Donor Transplants with Donor Age > 55 years: 1988 –2003 % 268% Transplant Year Vasudev et al, ATC 2005, Abstract # 1001

  23. Long-term Kidney Transplant Survival Deceased Donor Transplants: 1988 – 2003 N =121,610 Post-transplant Years Vasudev et al, ATC 2005, Abstract # 1001

  24. Donor age and renal function Creatinine clearance at 3 years 100 % 80 % > 59 ml/min 60 % 30-59 ml/min < 30 ml/min 40 % dialysis 20 % dead 0 % < 20 20-29 30-39 40-49 50-59 60-69 > 69 Donor age (years) RMRC (informe estadístic 1999)

  25. Cadaveric Renal Transplant Survival Overall  42% SCr <1.5mg/dL:  74% SCr >1.5mg/dL:  21% 19.0 11.2 10.9 7.5 6.2 7.9 Hariharan et al. Kidney Int: 62:311-18, 2002

  26. Renal dysfunction is a strong risk factor for cardiovascular death CV death with a functioning graft 3.0 *p<0.05 2.5 2.26* 2.0 1.67* 1.49* 1.5 1.37* RR 1.19* 1.03 1.00 1.0 0.5 0 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 Serum creatinine (mg/dL) Adapted from Meier-Kriesche HU, et al. Transplantation 2003;75:1291–5

  27. Gill J et al. Kidney International 2005 (in press)

  28. All Transplants Transplants with Functioning Graft At 3 months Transplants with Functioning Graft At 12 months Kasiske et al, AJT 2005 (in press)

  29. 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)

  30. 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)

  31. Maintenance Therapy at Baseline – First Solitary Transplants 1995-2002 80 70 60 Relative Frequency 50 40 30 80 20 10 0.7 Year of Transplant 70 1995 0 1996 60 45.7 1997 1996 50 1997 1998 1998 40 Relative Frequency 24.0 1999 30 2000 20 6.0 5.2 3.4 3.2 2.5 2001 10 2002 0 CSA Only FK Only RAPA / MMF FK / RAPA CSA / RAPA CSA / MMF FK / MMF * Other regiments not displayed Maintenance Therapies*

  32. Jak3i ? imTOR LEA ICN MPA Ac policlonales FK778 Acm anti-IL2R

  33. Introducción de xenobióticos en trasplante de órganos imTOR MMF ICN AZA 2000 med 90s 80s 60s

  34. Introducción de xenobióticos en trasplante de órganos CNI ? MMF imTOR AZA 2000 med 90s 80s 60s Uso transitorio de ICN?

  35. ICN en trasplante renal • Serendipity • El azar y la necesidad (Monod) • Identificar grandes éxitos detrás de pequeños fracasos

  36. Inhibición de la activación célula T en IS ? ICN NFAT ILs

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