A Potential Route to Reduce Ischemia/Reperfusion Injury in Organ Preservation

The pathophysiological process of ischemia and reperfusion injury (IRI), an inevitable step in organ transplantation, causes important biochemical and structural changes that can result in serious organ damage. IRI is relevant for early graft dysfunction and graft survival. Today, in a global context of organ shortages, most organs come from extended criteria donors (ECDs), which are more sensitive to IRI. The main objective of organ preservation solutions is to protect against IRI through the application of specific, nonphysiological components, under conditions of no blood or oxygen, and then under conditions of metabolic reduction by hypothermia. The composition of hypothermic solutions includes osmotic and oncotic buffering components, and they are intracellular (rich in potassium) or extracellular (rich in sodium). However, above all, they all contain the same type of components intended to protect against IRI, such as glutathione, adenosine and allopurinol. These components have not changed for more than 30 years, even though our knowledge of IRI, and much of the relevant literature, questions their stability or efficacy. In addition, several pharmacological molecules have been the subjects of preclinical studies to optimize this protection. Among them, trimetazidine, tacrolimus and carvedilol have shown the most benefits. In fact, these drugs are already in clinical use, and it is a question of repositioning them for this novel use, without additional risk. This new strategy of including them would allow us to shift from cold storage solutions to cold preservation solutions including multitarget pharmacological components, offering protection against IRI and thus protecting today's more vulnerable organs

IGL-1 solution reduces endoplasmic reticulum stress and apoptosis in rat liver transplantation

Injury due to cold ischemia reperfusion (I/R) is a major cause of primary graft non-function following liver transplantation. We postulated that I/R-induced cellular damage during liver transplantation might affect the secretory pathway, particularly at the endoplasmic reticulum (ER). We examined the involvement of ER stress in organ preservation, and compared cold storage in University of Wisconsin (UW) solution and in Institute Georges Lopez-1 (IGL-1) solution. In one group of rats, livers were preserved in UW solution for 8 h at 4 °C, and then orthotopic liver transplantation was performed according to Kamada's cuff technique. In another group, livers were preserved in IGL-1 solution. The effect of each preservation solution on the induction of ER stress, hepatic injury, mitochondrial damage and cell death was evaluated. As expected, we found increased ER stress after liver transplantation. IGL-1 solution significantly attenuated ER damage by reducing the activation of three pathways of unfolded protein response and their effector molecules caspase-12, C/EBP homologous protein-10, X-box-binding protein 1, tumor necrosis factor-associated factor 2 and eukaryotic translation initiation factor 2. This attenuation of ER stress was associated with a reduction in hepatic injury and cell death. Our results show that IGL-1 solution may be a useful means to circumvent excessive ER stress reactions associated with liver transplantation, and may optimize graft quality

Renal ischemic preconditioning improves recovery of kidney function and decreases alpha-smooth muscle actin expression in a rat model

PURPOSE: We determined the role of ischemic preconditioning on renal function and histology in a rat model. MATERIALS AND METHODS: A total of 34 Sprague-Dawley rats (Janvier Laboratories, Le Genet-St-Isle, France) were divided into 6 groups, including sham operation, ischemic preconditioning alone (5 minutes of bilateral ischemia followed by 5 minutes of reperfusion for 3 cycles), ischemia alone (60 minutes of bilateral renal pedicle clamping), ischemic preconditioning before bilateral ischemia, ischemic preconditioning before ischemia in left nephrectomized rats and ischemic preconditioning of the left kidney alone before 60 minutes of bilateral warm ischemia to assess the effect of left kidney preconditioning on the contralateral kidney. Serum creatinine and malondialdehyde levels were recorded at days 0, 1, 3, 11 and 15. Kidneys were harvested at day 15 for histological study and alpha-smooth muscle actin typing. RESULTS: At days 1 and 3 serum creatinine and malondialdehyde levels were significantly lower in the ischemic preconditioning group compared to levels in the ischemia alone group. At days 11 and 15 creatinine and malondialdehyde levels were similar in all groups and comparable to levels at day 0. At day 15 ischemic preconditioning kidneys showed significantly decreased fibrosis and alpha-smooth muscle actin expression than ischemia alone kidneys. CONCLUSIONS: Ischemic preconditioning improves the ability of rat kidney to tolerate subsequent ischemic injury in the first 3 days after reperfusion. Moreover, fibrosis and alpha-smooth muscle actin expression are decreased in ischemic preconditioning kidneys 15 days after reperfusion, suggesting a potential interest of ischemic preconditioning in surgical situations that expose kidneys to prolonged warm ischemia