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

Como o próprio titulo indica (sugere) o nosso estudo pretendeu essencialmente constituir-se como (começou por ser) uma análise critica da nossa experiência. Esta, estávamos absolutamente seguros disso, iria fornecer-nos os dados para responder às questões: porque o fizemos? Como o fizemos? Quais os resultados? Que alternativas? Por outras palavras interessava-nos detectar problemas, inventariar questões e encontrar soluções que poderão contribuir para a melhoria objectiva dos nossos procedimentos técnico-científicos e consequentemente dos nossos resultados.

Inmunosupresión convencional AZA-CS Inicios del trasplante hasta mediados 80

Jean-François Borel propiedades inmunossupressoras de la ciclosporina (1972) Como o próprio titulo indica (sugere) o nosso estudo pretendeu essencialmente constituir-se como (começou por ser) uma análise critica da nossa experiência. Esta, estávamos absolutamente seguros disso, iria fornecer-nos os dados para responder às questões: porque o fizemos? Como o fizemos? Quais os resultados? Que alternativas? Por outras palavras interessava-nos detectar problemas, inventariar questões e encontrar soluções que poderão contribuir para a melhoria objectiva dos nossos procedimentos técnico-científicos e consequentemente dos nossos resultados.

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. Como o próprio titulo indica (sugere) o nosso estudo pretendeu essencialmente constituir-se como (começou por ser) uma análise critica da nossa experiência. Esta, estávamos absolutamente seguros disso, iria fornecer-nos os dados para responder às questões: porque o fizemos? Como o fizemos? Quais os resultados? Que alternativas? Por outras palavras interessava-nos detectar problemas, inventariar questões e encontrar soluções que poderão contribuir para a melhoria objectiva dos nossos procedimentos técnico-científicos e consequentemente dos nossos resultados.

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.

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

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

First cadaveric graft survival (P <0.025). 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

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

Renal allograft half-life Death censored N=98 340 pacientes Hariharan, NEJM 2000

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 Semiquantitative estimation of effects of immunosuppressants on cardiovascular risk factors Immunosuppressants have differential effects on CV risk factors. In optimising immunosuppressive regimens, consideration should be given to choose those least likely to increase CV risk, e.g. tapering/discontinuing corticosteroids or ciclosporin, or replacing ciclosporin with tacrolimus. Reference: Fellström B. Risk factors for and management of post-transplantation cardiovascular disease. BioDrugs 2001;15:261–78 – = none; + = slight; ++ = moderate; +++ = severe Adapted from Fellström B. BioDrugs 2001;15:261–78

Post-transplant blood pressure is a predictor of long-term graft survival 100 90 80 70 60 50 One-year systolic blood pressure (mmHg) < 120 120-129 130-139 140-149 150-159 160-169 170-179 ≥ 180 N=2805 N=4488 N=5961 N=6670 N=4443 N=2925 N=1217 N=1242 Functional grafts surviving (%) In a study by Opelz et al. in 29,651 renal transplant patients it was shown that post-transplant blood pressure is a highly significant predictor of long-term kidney graft survival. Patients with the lowest post-transplant blood pressure (<120 mmHg) had the best chance of functional graft survival and the chance of survival decreased as the blood pressure increased. Another study by Peschke et al. underlined the association between hypertension and poorer renal graft function during the first 5 years following transplantation. References: Opelz G, Wujciak T, Ritz E, et al., for the Collaborative Transplant Study. Association of chronic kidney graft failure with recipient blood pressure. Kidney International 1998;53:217-222 Peschke B, Scheuermann EH, Geiger H, et al. Hypertension is associated with hyperlipidemia, coronary heart disease and chronic graft failure in kidney transplant recipients. Clinical Nephrology 1999;51:290-295 1 2 3 4 5 6 7 Time (years) Reproduced from Opelz G, et al. Kidney Int 1998;53:217–22

Cardiovascular mortality in renal transplant recipients 10 1 0.1 0.01 0.001 Annual mortality (%) Renal transplant recipients General population Data on renal transplant patients from the US Renal Data System (USRDS) have shown that renal transplant patients have a higher risk of mortality compared to the general population. This risk increases with the age of the recipient, but the risk should not be underestimated in younger patients. Compared with the general population, cardiovascular mortality in transplant patients is increased almost 10-times between the ages of 35 and 44 years and is at least doubled between the ages of 55 and 64 years. Reference: Foley RN, Parfrey PS, Samak MJ. Cardiovascular disease in chronic renal disease. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32(Suppl. 3):S112–19 25–34 35–44 45–54 55–64 65–74 75–84 Age (years) 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 69,321 US nonrenal transplants (1990-2000) CRF defined as GFR < 29 ml/min/1.73m2 Ojo AO et al. NEJM, 2003

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

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

Creatinine clearance at 3 years 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)

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

Renal dysfunction is a strong risk factor for cardiovascular death 3.0 CV death with a functioning graft *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 An analysis on 58,900 kidney adult patients registered in the USRDS database was performed. All patients received a primary renal transplant between 1988 and 1998 and had at least one year of graft survival Serum creatinine values at 1 year after transplantation were strongly associated with the risk for cardiovascular death. Reference: Meier-Kriesche HU, Baliga R, Kaplan B. Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation 2003;75:1291-1295 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

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

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

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)

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 1996 60 1996 45.7 1997 50 1997 1998 Relative Frequency 40 1998 24.0 1999 30 2000 20 6.0 5.2 3.4 3.2 2.5 2001 10 2002 RAPA / MMF CSA Only FK Only FK / RAPA CSA / RAPA CSA / MMF FK / MMF * Other regiments not displayed Maintenance Therapies*

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

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

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

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

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