integrating-continuous-renal-replacement-therapy-into-ex-situ

Integrating Continuous Renal Replacement Therapy into <em>Ex-situ</em> Normothermic Liver Machine Perfusion

Ex situ normothermic machine perfusion (NMP) of the liver has emerged as a dynamic preservation strategy, enabling the maintenance of metabolic activity ...

University of Barcelona

Hospital Universitario La Paz

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)

The hepatic sinusoid: The "muse" in small-for-size liver transplantation.

Liver resection treats primary and secondary liver tumors, though clinical applicability is limited by the remnant liver mass and quality. Herein, major hepatic resections were performed in pigs to define changes associated with sufficient and insufficient remnants and improve liver-specific outcomes with somatostatin therapy. Three experimental groups were performed: 75% hepatectomy (75H), 90% hepatectomy (90H), and 90% hepatectomy + somatostatin (90H + SST). Animals were followed for 24 h (N = 6) and 5 d (N = 6). After hepatectomy, portal pressure gradient was higher in 90H versus 75H and 90H + SST (8 (3-13) mmHg vs. 4 (2-6) mmHg and 4 (2-6) mmHg, respectively,  < 0.001). After 24 h, changes were observed in 90H associated with stellate cell activation and collapse of sinusoidal lumen. Collagen chain type 1 alpha 1 mRNA expression was higher, extracellular matrix width less, and percentage of collagen-staining areas greater at 24 h in 90H versus 75H and 90H + SST. After 5 d, remnant liver mass was higher in 75H and 90H + SST versus 90H, and Ki-67 immunostaining was higher in 90H + SST versus 75H and 90H. As well, more TUNEL-staining cells were observed in 90H versus 75H and 90H + SST at 5 d. Perioperative somatostatin modified portal pressure, injury, apoptosis, and stellate cell activation, stemming changes related to hepatic fibrogenesis seen in liver remnants not receiving treatment.

Somatostatin Therapy Improves Stellate Cell Activation and Early Fibrogenesis in a Preclinical Model of Extended Major Hepatectomy.

The past decade has been the foreground for a radical revolution in the field of preservation in abdominal organ transplantation. Perfusion has increasingly replaced static cold storage as the preferred and even gold standard preservation method for marginal-quality organs. Perfusion is dynamic and offers several advantages in comparison with static cold storage. These include the ability to provide a continuous supply of new metabolic substrates, clear metabolic waste products, and perform some degree of organ viability assessment before actual transplantation in the recipient. At the same time, the ongoing importance of static cold storage cannot be overlooked, in particular when it comes to logistical and technical convenience and cost, not to mention the fact that it continues to work well for the majority of transplant allografts. The present review article provides an overview of the fundamental concepts of organ preservation, providing a brief history of static cold preservation and description of the principles behind and basic components of cold preservation solutions. An evaluation of current evidence supporting the use of different preservation solutions in abdominal organ transplantation is provided. As well, the range of solutions used for machine perfusion of abdominal organs is described, as are variations in their compositions related to changing metabolic needs paralleling the raising of the temperature of the perfusate from hypothermic to normothermic range. Finally, appraisal of new preservation solutions that are on the horizon is provided.

Abdominal Organ Preservation Solutions in the Age of Machine Perfusion.

Static cold storage (SCS) remains the most widely used method of liver graft preservation due to its simplicity, accessibility, and reduced cost in transplantation practice. Since the invention of the University of Wisconsin (UW) solution, several alternative preservation solutions-including histidine-tryptophan-ketoglutarate (HTK), Celsior, and more recently IGL-1 and IGL-2-have been formulated to optimize cellular and vascular protection during cold ischemia. More recently, the introduction of dynamic perfusion techniques, such as hypothermic oxygenated perfusion (HOPE) and normothermic machine perfusion (NMP), approximately fifteen years ago, has further enhanced transplantation protocols, being applied either alone or in combination with traditional SCS to ensure optimal graft preservation prior to implantation. Despite these technological advances, achieving fully effective dynamic perfusion remains a key challenge for improving outcomes in vulnerable grafts, particularly steatotic or marginal livers. This review details how Polyethylene Glycol 35 (PEG35)-based solutions activate multiple cytoprotective pathways during SCS, including AMP-activated protein kinase (AMPK), nitric oxide (NO) production, and the antioxidant transcription factor Nrf2. We propose that these molecular mechanisms serve as a form of preconditioning that is synergistically leveraged by HOPE to preserve mitochondrial function, endothelial glycocalyx integrity, and microvascular homeostasis. Furthermore, the oncotic and rheological properties of PEG35 reduce perfusate viscosity, mitigating shear stress and microcirculatory damage during dynamic perfusion-effects that are further enhanced by NO- and AMPK-mediated protection initiated during the SCS phase. This integrated approach provides a strong rationale for combining PEG35-mediated SCS with HOPE, particularly for grafts with high susceptibility to ischemia-reperfusion injury, such as fatty livers. Finally, we highlight emerging avenues in graft preservation, including the design of unified perfusion solutions that optimize endothelial, mitochondrial, and redox protection, with the potential to improve post-transplant outcomes and extend applicability to other solid organ grafts.

Article	Year
The hepatic sinusoid: The "muse" in small-for-size liver transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons\| PubMed ID: 33512050	2021
Somatostatin Therapy Improves Stellate Cell Activation and Early Fibrogenesis in a Preclinical Model of Extended Major Hepatectomy. Cancers\| PubMed ID: 34439143	2021
Abdominal Organ Preservation Solutions in the Age of Machine Perfusion. Transplantation\| PubMed ID: 35939388	2023
Static Cold Storage and Machine Perfusion: Redefining the Role of Preservation and Perfusate Solutions. International journal of molecular sciences\| PubMed ID: 41373885	2025

Jordi Vengohechea

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