Cell therapy based on stem cells or their extracellular vesicles during kidney graft preservation: Current state of the art and novelties

Abstract

Transplantation often remains the best therapeutic option in terms of life quality and disease prognosis improvement to treat chronic or even acute organ failure. According to a report published by the World Health Organization in 2023,¹ less than 10% of the world's organ needs are covered. Focusing on the kidney, which is now the most transplanted organ in the world, the latest report of the Global Observatory on Donation and Transplantation published in 2023 (based on 2022 data)² pointed out the gap between supply and demand: there are currently more patients on the active waiting list than there are grafts available for them worldwide. Kidney grafts can come from two main different sources: living donors, which represent a minority of donations, and deceased donors. Nevertheless, the organ shortage, which has been worsening year after year, has led to extend donation criteria over the years. This means, for example, the use of deceased donors not only after brainstem death but also after unpredictable irreversible circulatory arrest with immediate cardiopulmonary resuscitation attempted by trained providers (according to the Maastricht classification, second category) and after circulatory arrest occurring based on a decision to withhold or withdraw life-sustaining treatment (according to the Maastricht classification, third category). These death circumstances are usually associated with intensive donor reanimation processes consisting in noradrenaline administration, in massive vascular filling to prevent reanimation complications such as inflammation, haemodynamic instability or acute kidney failure. Extended criteria donors also include older donors aged over 65 years and donors with comorbidities such as arterial hypertension, cardiopathy, diabetes and even chronic kidney failure. The growing need for organs may also result in organs being transported from more distant regions. In all these situations kidney grafts are more susceptible to be affected by ischaemia‒reperfusion (IR) injuries.

IR is a pathophysiological phenomenon taking place from the donor's reanimation to the recipient's transplantation. Ischaemia is induced by the sudden arrest of oxygen and nutrients supply during the organ retrieval step, which may be prolonged during organ preservation sequence depending on its modalities. Reperfusion occurs when anastomoses are performed between the graft and the recipient and refers to the massive oxygen supply in a medium, which was previously deprived of oxygen.³ On a microscopic scale, this phenomenon is associated with shifts in mitochondrial metabolism and function, by a release of reactive oxidative species causing cytoskeleton destruction, complement system activation and recruitment of innate and adaptative immune cells.⁴ Faced with these perturbations, the cell eventually dies by necrosis, phagocytosis or apoptosis. On a macroscopic scale considering renal grafts, IR mainly leads to graft endothelial injuries, which can be further translated clinically by acute tubular necrosis, primary non-function or delayed graft function usually characterised by the use of dialysis in the 7 days post-transplantation. Because of these injuries and immune system activation, IR can be responsible for shorter graft survival and even acute or chronic graft rejection.⁴

Since 2000s, researchers have developed several techniques to improve kidney graft conditioning to counteract IR-induced kidney injuries. From cold storage, which has been the main preservation strategy for decades, dynamic hypothermic machine perfusion (HMP) has greatly improved graft conditioning.⁵ According to the Arrhenius's equation, hypothermia causes a 50% decrease of cell metabolic activity every 10°C. Placed in an iso-osmotic extracellular preservation liquid at a mean temperature of 4°C, the renal graft is connected to the preservation solution with its artery and a surgical aortic patch, then the blood is reabsorbed into the venous system, thus allowing continuous kidney perfusion. This technology has increased the microcirculation in the graft, reduced delayed graft function, chronic graft dysfunction and ensured a better graft survival at 1 year compared to standard static cold storage (SCS) in deceased donor kidney transplantation.^{5, 6}

Normothermic machine perfusion (NMP) has also emerged as a new strategy to optimise graft preservation. It is defined by a warmed oxygenated circulation at a mean temperature between 34°C and 37°C through the kidney to recreate near-physiological conditions.⁷ Oxygen can be delivered by using either whole blood, pyridoxylated bovine haemoglobin or a combination of preservation solution and purified red blood cells.⁸ It has been shown to be feasible and safe in a randomised clinical trial.⁷ Furthermore, NMP has several advantages compared to SCS and HMP techniques. NMP can help cells to maintain an aerobic metabolism to minimise ischaemia-induced damage. Graft perfusion parameters, temperature and other items can also be monitored in real time through NMP. It is also a way to deliver therapeutics including those based on cell therapy.⁹

In the field of organ transplantation, cell therapy has emerged in recent years as a promising option for the future of graft preservation in dynamic perfusion.

Although stem cell-derived EVs have emerged as a promising new strategy in the field of organ conditioning in transplantation, pharmacokinetic and pharmacodynamic challenges still remain to fill the knowledge gap in terms of mechanistic understanding, as well as isolation and characterisation techniques need to be further developed to promote a clinical use of EVs.

However, such an approach first requires serious thinking about precise criteria to define the organs at risk of IR injury and delayed graft function. Furthermore, this entails a better harmonisation of reanimation, surgical and clinical practice between the different centres. Therefore, marginal grafts could be selected for the most optimal preservation protocol regarding the donor/recipient's clinical context and be repaired prior transplantation. In this way, in a future ageing society affected by a more severe organ shortage, the cell therapy approach combined with the improvement of graft dynamic preservation technologies may be a supplemental potential mean to optimise the transplantation procedure from extended criteria donors or long-distance grafts.

NCB wrote the initial draft of this manuscript; TH and CS reviewed the manuscript. All authors approved the final version of this review.

Not applicable (review).