Diagnostic criteria of antibody-mediated rejection in kidney transplants.

The diagnosis and treatment of anti-donor antibody-mediated rejection or humoral rejection (ABMR) is one of the main discussions at the moment in kidney transplantation. The search for histopathological markers that help us to diagnose ABMR has been more problematic, in contrast to the histological expression of cellular or tubulointerstitial rejection. Although the relationship between post-transplant anti-donor antibodies and the allograft's prognosis has been a topic of discussion for a long time, led in the main by P.Terasaki, it was not until the beginning of 1990s when P. Halloran studied the humoral mechanisms of rejection in greater depth. Feutch described the importance of C4d deposits as a marker that shows a humoral mechanism of allograft rejection in 1993. As a result of many studies carried out, the Banff consensus group established some diagnostic histopathological criteria of acute (ABMR) in 2003. These have been modified slightly in later meetings of the group. Furthermore, in 2005 this same working group looked at the physiopathological mechanisms causing chronic allograft failure in more detail and established the criteria defining chronic humoral rejection. In this review, we are trying to update any useful histopathological criteria for diagnosing acute and chronic ABMR.

[Renal xenotransplant. Acute vascular rejection]. / Xenotrasplante renal. El rechazo vascular agudo.

INTRODUCTION AND OBJECTIVES: Organ transplant is nowadays a usual and succesful practice, although with limited application due to the lack of organs. Yearly thousands of patients get access to the waiting list and finally will death while they are waiting for an organ. In the U.S.A., 2005 waiting list for kidneys, heart, liver lung and pancreas was around 94.419. Number of transplants performed was 27.966 and died patients while waiting for an organ, 41.392 (1). Pig xenotransplant is one of the possibilities to ameliorate the lack of organs for transplant. Arrangement of pigs with different genetic modifications generated great expectatives on the use of these organs in clinics. Although preclinical experimental studies with kidneys reached prolonged survivals, these are really insufficient to go on with the clinical appliance. Hyperacute rejection produces destruction of the organ immediately. This problem could be pharmacologically precluded in xeno-transplant. However, acute rejection or vascular rejection usually produces the lost of the implant. New inmunosuppresive schedules delay significantly rejection, but not definitively. Xenotransplant as a therapeutic option introduces important scientific problems, as well as ethical and social. This paper reports a summary of our experience in renal xenotransplant and the management of acute rejection. MATERIAL AND METHODS: Twenty xenotransplants from transgenic pig (hDAF) as donor to babuine as receptor. Average weight of the animals ranged 11.4-75 kgrs and babuines 10-26 kg. Xenograft average weight ranged 39-160 grs. Implant was performed to aorta and cava. Four inmunosupressive schedules were used. RESULTS: Average survival was 7-9 days. Final Histological findings are described. Changes observed were secondary to acute tubular necrosis mixed with changes due to acute rejection. Three grafts were lost due to technical major problems. CONCLUSIONS: Although we have observed some promising results, xenotransplant is a very difficult problem to solve in the long-term. A lot of research is still needed-.

Xenotrasplante renal. El rechazo vascular agudo / Renal xenotransplant. Acute vascular rejection

Introducción y objetivos: El trasplante de órganos es hoy una práctica habitual y de éxito, pero de aplicación limitada, debido a la insuficiencia de órganos. Anualmente miles de pacientes en lista de espera fallecen, esperando un órgano. En EEUU en el 2005 la lista de espera para trasplantes de órganos, riñón, corazón, hígado, pulmón, páncreas era de 94.419. El número de trasplantes realizados fue de 27.966 y el de fallecidos esperando un órgano 41.392. (1) El xenotrasplante de órganos de cerdo es una de las esperanzas para aliviar la falta de órganos para el trasplante. La disponibilidad de cerdos con distintas modificaciones genéticas, creó grandes expectativas sobre una pronta utilización clínica de los mismos, sin embargo, aunque los estudios experimentales preclínicos con el riñón han alcanzado supervivencias prolongadas, estas son insuficientes para dar el paso a la fase clínica. El rechazo hiperagudo (RH) con destrucción del órgano de forma inmediata, habitual en el trasplante de órganos entre especies distintas filogenéticamente (trasplante discordante) puede en la actualidad ser evitado sin embargo, la aparición de un posterior rechazo humoral agudo (RHA) también llamado rechazo vascular agudo (RVA) o xenorechazo agudo retardado, da lugar al fracaso del xenotrasplante. La utilización de distintas pautas de inmunosupresión han conseguido retrasar de forma significativa este rechazo, pero no lo previenen de forma sistemática. El xenotrasplante como opción terapéutica plantea importantes problemas científicos, éticos y sociales. En este artículo exponemos un resumen de nuestra experiencia en xenotrasplante renal y comentamos los problemas del RVA. Material y método: Se han practicado 20 xenotrasplantes renales de cerdo transgénico hDAF (donante) a babuino (receptor). El peso de los cerdos osciló entre 11,400 y 75 kg. y el de los babuinos entre 10 y 26,500 kg. El peso del xenoinjerto, riñón del cerdo, osciló entre 39 y 160 g. Resultados: La supervivencia media de los animales estuvo entre 7-9 días. El estudio histológico final de los injertos mostró cambios secundarios a necrosis tubular aguda mezclados con alteraciones propias de rechazo agudo. Tres injertos se perdieron por problemas técnicos mayores. Conclusiones: Aunque hemos observado resultados prometedores, el xenotrasplante es una cuestión de gran dificultad, especialmente a largo plazo. Se precisa aún en la actualidad de mucha actividad investigadora en este campo

Introduction and objectives: Organ transplant is nowadays a usual and succesful practice, although with limited application due to the lack of organs. Yearly thousands of patients get access to the waiting list and finally will death while they are waiting for an organ. In USA, 2005 waiting list for kidneys, heart, liver lung and pancreas was around 94.419. Number of transplants performed was 27.966 and died patients while waiting for an organ, 41.392 (1). Pig xenotransplant is one of the possibilities to ameliorate the lack of organs for transplant. Arrangement of pigs with different genetic modifications generated great expectatives on the use of these organs in clinics. Although preclinical experimental studies with kidneys reached prolonged survivals, these are really insufficient to go on with the clinical appliance. Hyperacute rejection produces destruction of the organ immediately. This problem could be pharmacologically precluded in xenotransplant. However, acute rejection or vascular rejection usually produces the lost of the implant. New inmunosuppresive schedules delay significantly rejection, but not definitively. Xenotransplant as a therapeutic option introduces important scientific problems, as well as ethical and social. This paper reports a summary of our experience in renal xenotransplant and the management of acute rejection. Material and methods: Twenty xenotransplants from transgenic pig (hDAF) as donor to babuine as receptor. Average weight of the animals ranged 11.4-75 kgrs and babuines 10-26 kg. Xenograft average weight ranged 39-160 grs. Implant was performed to aorta and cava. Four inmunosupressive schedules were used. Results: Average survival was 7-9 days. Final Histological findings are described. Changes observed were secondary to acute tubular necrosis mixed with changes due to acute rejection. Three grafts were lost due to technical major problems. Conclusions: Although we have observed some promising results, xenotransplant is a very difficult problem to solve in the long-term. A lot of research is still needed

[Renal xenotransplantation from hDAF pig to baboon. Experience and review]. / Xenotrasplante renal cerdo hDAF-babuino. Experiencia y revisión.

UNLABELLED: The renal xenotransplant could be the solution on the demand of organs for transplantation. We present here our experience and review the actual status of the xenotransplant. METHODS: We have done 20 xenotransplants from transgenic pig h DAF to baboons, with four protocols of immunosuppression. All the hosts were treated with GAS 914. Group A: Cyclophosphamide, Cyclosporine, Mycophenolate, and Steroids (n = 10). Group B: Cyclophosphamide, Cyclosporine, FTY 720, and Steroids (n = 3). Group C: Basiliximab, Cyclosporine, Mycophenolate, and Steroids (n = 3). Group D: Basiliximab, FTY 720, Everolymus, and Steroids (n = 4). RESULTS: The duration of the xenografts ranged between 1 and 31 days. The function of the xenografts in relation to the type of immunosuppression were not significantly different: A) 7 days, B) 8 days, C) 8 days, and D) 9 days. CONCLUSIONS: 1. The cold ischemic time of the graft, has influence in the initial function of the kidneys but not in the evolution and duration of the graft. 2. The hyperacute rejection has been overcome with the utilization of transgenic pigs. The graft failure was due to acute humoral rejection that was not aborted by the actual inmunosupressors. 3. It is necessary to develop new immunosuppression protocols, through new knowledge of their pharmacology and the physiology of the xenografts, and at the same time it is important to avoid the potential risk of transmission of animal infections.

Influence of the management of asystolic donors on kidney transplantation outcome.

Two methods of donor management were analysed, namely, with and without in situ cooling perfusion of the kidney in an attempt to determine the optimal management and preservation methods for asystolic kidney donors. The group of recipients of in situ cooling perfusion kidneys showed more days of oliguria (P <.05), needed more dialysis sessions (P <.05), and showed no transplant function during the first week after surgery. This group also had a greater probability of acute rejection (P =.071) and a higher rate of nonfunctioning grafts (P =.09). We conclude that in situ cooling perfusion of asystolic kidney donors impairs graft function.

Autopsy-determined causes of death in solid organ transplant recipients.

The aim of this study was to review the main causes of death as determined by autopsy of deceased solid organ transplant recipients. We reviewed 156 autopsies including 76 heart, 32 liver, 29 kidney, and 19 lung transplant recipients. The mean survival period varied depending on the transplanted organ: namely heart, 497 days; liver, 189 days; kidney, 1124 days; and lung, 252 days. Infections were the most common cause of death in all groups, varying from 21% in heart to 63% in lung recipients. Acute rejection, chronic rejection, and malignancies only appeared as the cause of death in heart recipients (14.5%, 9.2%, and 4%, respectively). Primary graft failure was present in heart (15.7%), kidney (3.4%), and lung (5.3%) recipients. The highest rate of surgical complications as a cause of death was observed in heart transplant recipients. In all groups there was a significant percentage (about 30%) of other pathologies that were responsible for death, such as pulmonary embolism, central nervous system pathology, acute pancreatitis, digestive hemorrhage, and acute myocardial infarction. Our results emphasize that infections are the main cause of death within the first year posttransplant, independent of the organ transplanted.

Xenotrasplante renal cerdo hDAF-babuino. Experiencia y revisión / Renal xenotrasplantation of HDAF pig to baboons. Experience and review

INTRODUCCIÓN: El xenotrasplante renal puede representar la solución a la creciente demanda de órganos. Presentamos nuestra experiencia y revisamos el estado actual del xenotrasplante. MATERIAL Y MÉTODO: Hemos realizado 20 xenotrasplantes de riñón de cerdo transgénico hDAF a babuino con cuatro protocolos de inmunosupresión. Todos los receptores recibieron GAS 914.Grupo A: Ciclofosfamida, Ciclosporina, Micofenolato y Corticosteroides (n=10).Grupo B: Ciclofosfamida, Ciclosporina, FTY 720 y Corticosteroides (n=3).Grupo C: Basiliximab, Ciclosporina, FTY 720 y Corticosteroides (n=3).Grupo D: Basiliximab, FTY 720, Everolimus y Corticosteroides (n=4). RESULTADOS: La supervivencia de los xenoinjertos osciló entre 1 y 31 días. La supervivencia en relación con los protocolos de inmunosupresión no fue significativamente diferente: A) 7 días, B) 8días, C) 8 días, D) 9 días. CONCLUSIONES: 1. Los tiempos de isquemia fría influyen en la función inicial de los riñones, no en su evolución final. 2. El rechazo hiperagudo ha sido superado con la utilización de cerdos transgénicos, produciéndose el fracaso por rechazo humoral agudo, no controlado con los protocolos de inmunosupresión actuales. 3. Es preciso investigar y desarrollar otros protocolos de inmunosupresión que nos permitan un mejor conocimiento de la fisiología del xenoinjerto y de su potencial riesgo de transmisión de enfermedades (AU)

SUMMARY: The renal xenotrasplant could be the solution on the demand of organs for transplantation. We present here our experience and review the actual status of the xenotransplant. METHODS: We have done 20 xenotransplants from transgenic pig h DAF to baboons, with four protocols of inmunosupression. All the hosts were treated with GAS 914.Group A: Cyclophosphamide, Cyclosporine, Mycophenolate, and Steroids (n=10).Group B: Cyclophosphamide, Cyclosporine, FTY 720, and Steroids (n=3). Group C: Basiliximab, Cyclosporine, Mycophenolate, and Steroids (n=3). Group D: Basiliximab, FTY 720, Everolymus, and Steroids (n=4). RESULTS: The duration of the xenografts ranged between 1 and 31 days. The function of the xenografts in relation to the type of inmunosupression were not significantly different: A) 7 days, B) 8 days, C) 8 days, and D) 9 days. CONCLUSIONS: 1. The cold ischemic time of the graft, has influence in the initial function of the kidneys but not in the evolution and duration of the graft. 2. The hyperacute rejection has been overcome with the utilization of transgenic pigs. The graft failure was due to acute humoral rejection that was not aborted by the actual inmunosupressors. 3. It is necessary to develop new inmunosupression protocols, through new knowledge of their pharmacology and the physiology of the xenografts, and at the same time it is important to avoid the potential risk of transmission of animal infections (AU)