Preservació del empelt i lesió per isquèmia reperfusió en el transplantament hepàtic. Estudis en inmunomodulació i atenuació de la injuria tisular
- Autores: Juan Andrés Echeverri Cifuentes
- Directores de la Tesis: Ramón Charco (dir. tes.), Markus Selzner (codir. tes.), Gonzalo Sapisochin (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2021
- Idioma: catalán
- Tribunal Calificador de la Tesis: Luis Grande Posa (presid.), Juan Carlos García-Valdecasas Salgado (secret.)
- Programa de doctorado: Programa de Doctorado en Cirugía y Ciencias Morfológicas por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Liver transplantation is the only treatment option for patients with end stage liver disease. The success of liver transplantation has led to organ shortage and increase of waiting list times for patients in need of this precious resource. Despite the efforts to increase the donor pool, many of these patients die or become de listed without even getting an organ offer. To palliate this problem, more liberal policies to use marginal grafts have been implemented with the risk of hampering post-transplant outcomes. These marginal grafts comprise organs from elderly donors, donation after cardiac death, or grafts with steatosis. Marginal grafts tolerate badly static cold storage, increasing post-transplant morbidity and mortality. Ex vivo machine perfusion is a promising tool to limit the complications associated with the use of marginal grafts.
Machine perfusion has the potential to reduce preservation injury, assess organ function and modify molecular pathways in the graft to improve post-transplant outcomes. Studies in porcine models and clinical trials have validated different types of perfusion techniques such as hypothermic oxygenated machine perfusion (HOPE), normothermic and sub-normothermic machine perfusion, and in situ normothermic regional perfusion. Each one of these techniques has benefits and limitations and are still under study as to which is better according to the type of organ perfused.
The optimal perfusion setup for ex-vivo machine preservation of liver grafts has not been defined yet. Despite numerous studies in porcine models and human clinical trials, no direct comparison has been done using different compositions of the perfusate. Adding anti-inflammatory agents plus sub-normothermic temperature could improve the protective effects of ex vivo organ perfusion. On the other hand, the use of vasodilators during ex vivo graft preservation has not been compared and validated among different perfusion setups. Vasodilators such as BQ123, Epoprostenol, and Verapamil reverse hepatic artery vasospasm caused by static cold storage and attenuate ischemia reperfusion injury. The optimal vasodilator to be used during ex vivo graft preservation with an effective and safe profile is still to be determined.
The aim of this doctoral thesis is to study the application of protective anti-inflammatory strategies and to compare different vasodilators used in porcine ex vivo preservation models. In the first phase of the study a group with a standard ex vivo setup used in human clinical trials was compared to a sub-normothermic group with added anti-inflammatory agents such as alprostadil, n-acetylcysteine, carbon monoxide, and sevoflurane. Livers perfused with the anti-inflammatory setup had less ischemia reperfusion injury and better post-transplant outcomes when compared with the standard perfusion setup. Addition of these components further improves warmed perfused preservation. In the second phase of the study, vasodilators used in current clinical trials (BQ123, Epoprostenol, and Verapamil) were compared to determine which one had the safest profile and better outcomes regarding ischemia reperfusion injury. Again, using a porcine ex vivo preservation model three different setups were compared. The use of BQ123, Verapamil, and Epoprostenol as vasodilators during normothermic ex vivo liver perfusion appeared to be safe and not harm standard criteria grafts. Livers perfused with BQ123 and Verapamil had higher hepatic artery flow and reduced endothelial cell and hepatocyte injury during ex vivo perfusion and in the posttransplant period compared to Epoprostenol.
