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Organ preservation; Transplantation; Ischemia-reperfusion injury; Machine perfusion; Hypothermic oxygenated perfusion; Normothermic machine perfusion; Supercooling; Cryopreservation; Organ viability

Introduction

Organ transplantation has revolutionized the treatment of end-stage organ failure, offering patients a chance at a significantly improved quality of life and extended survival. However, a critical bottleneck in transplantation is the limited supply of suitable donor organs coupled with the limitations of current preservation techniques [1]. Static cold storage (SCS), the conventional method for organ preservation, involves immersing the organ in a cold preservation solution and storing it at 4°C. While SCS has been instrumental in enabling transplantation, it induces cellular damage due to ischemia (lack of blood flow) and subsequent reperfusion injury (damage upon restoration of blood flow) [2]. This injury can lead to delayed graft function, increased risk of rejection, and ultimately, graft loss. The duration of safe preservation under SCS is limited, varying depending on the organ type, with hearts and lungs being particularly vulnerable [3]. This short timeframe restricts the geographical distance organs can be transported and limits the time available for recipient-donor matching and surgical preparation.

Description

To overcome the limitations of SCS, innovative preservation techniques have emerged, most notably machine perfusion (MP). MP involves perfusing the organ with a preservation solution at controlled temperature and pressure, providing continuous oxygen and nutrients to the cells [4]. This approach has shown promising results in various organ types, including kidneys, livers, and hearts. Hypothermic machine perfusion (HMP), typically performed at temperatures between 4°C and 8°C, has demonstrated superior outcomes compared to SCS, reducing delayed graft function and improving early graft function, especially in kidney transplantation [5]. Normothermic machine perfusion (NMP), performed at physiological temperatures (37°C), allows for functional assessment of the organ before transplantation, providing valuable information about its viability [6]. NMP also offers the potential for organ repair and reconditioning before transplantation, for example, by delivering therapeutic agents or performing gene therapy. Studies have shown that NMP can significantly improve outcomes in liver transplantation, particularly in marginal grafts [7]. Another promising advancement is hypothermic oxygenated perfusion (HOPE), which involves perfusing the organ with an oxygenated solution at hypothermic temperatures. HOPE has been shown to reduce ischemia-reperfusion injury and improve graft function in various organs [8].

Discussion

The mechanisms by which these innovative preservation techniques improve outcomes are multifaceted. MP, by providing continuous perfusion, minimizes ischemic damage by delivering oxygen and nutrients, removing metabolic waste products, and maintaining cellular metabolism. This active perfusion also reduces the inflammatory response associated with reperfusion injury. NMP offers the added advantage of allowing for functional assessment of the organ, which can help in better donor-recipient matching and prevent the transplantation of non-viable organs. This functional assessment can include measurement of bile production in livers, urine output in kidneys, and cardiac function in hearts. HOPE, by providing oxygen at hypothermic temperatures, enhances cellular metabolism and reduces oxidative stress, a key component of ischemia-reperfusion injury.

Beyond these established techniques, other promising strategies are being explored. Supercooling, which involves cooling organs below the freezing point without ice formation, has shown potential for extending preservation times [9]. However, challenges related to ice nucleation and toxicity of cryoprotective agents need to be addressed before clinical application. Cryopreservation, the preservation of organs at ultra-low temperatures using cryoprotective agents, offers the theoretical possibility of indefinite storage. However, achieving successful cryopreservation of whole organs remains a significant challenge due to the complex nature of organ structure and the toxicity of cryoprotective agents [10].

Future research in organ preservation should focus on several key areas. Further optimization of MP protocols, including the composition of perfusion solutions, temperature control, and perfusion parameters, is crucial. The development of biomarkers for assessing organ viability during preservation is also essential for improving donor-recipient matching and preventing the transplantation of non-viable organs. Further investigation into the mechanisms of ischemia-reperfusion injury and the protective effects of novel preservation techniques is necessary to develop more targeted interventions. The development of less toxic and more effective cryoprotective agents is crucial for advancing cryopreservation technology. Finally, large-scale clinical trials are needed to validate the efficacy and safety of these innovative preservation techniques and to establish their role in routine clinical practice.

Conclusion

Innovations in organ preservation, particularly MP and HOPE, have significantly improved transplant outcomes by mitigating ischemia-reperfusion injury and extending preservation times. These advancements offer the potential to expand the donor pool, improve organ utilization, and ultimately increase the number of successful transplants. Continued research and development in this field are essential to further optimize preservation techniques, develop novel strategies, and ultimately improve the lives of patients awaiting organ transplantation.

Acknowledgement

None

Conflict of Interest

None

References

1. Zielińska K, Kukulski L, Wróbel M, Przybyłowski P, Rokicka D, et al. (2022) Carbohydrate Metabolism Disorders in Relation to Cardiac Allograft Vasculopathy (CAV) Intensification in Heart Transplant Patients According to the Grading Scheme Developed by the International Society for Heart and Lung Transplantation (ISHLT). Ann Transplant 27: 933420.

Indexed at, Google Scholar, Crossref

2. Raffa GM, Di Gesaro G, Sciacca S, Tuzzolino F, Turrisi M, et al. (2016) Heart transplant program at IRCCS-ISMETT: Impact of mechanical circulatory support on pre- and post -transplant survival. Int J Cardiol 219: 358-361.

Indexed at, Google Scholar, Crossref

3. Kitamura S (2012) Heart transplantation in Japan: a critical appraisal for the results and future prospects. Gen Thorac Cardiovasc Surg 60: 639-644.

Indexed at, Google Scholar, Crossref

4. Delgado JF, Reyne AG, de Dios S, López-Medrano F, Jurado A, et al. (2015) Influence of cytomegalovirus infection in the development of cardiac allograft vasculopathy after heart transplantation. J Heart Lung Transplant 3:1112-1119.

Indexed at, Google Scholar, Crossref

5. Wever-Pinzon O, Edwards LB, Taylor DO, Kfoury AG, Drakos SG, et al. (2017) Association of recipient age and causes of heart transplant mortality: Implications for personalization of post-transplant management-An analysis of the International Society for Heart and Lung Transplantation Registry. J Heart Lung Transplant 36: 407-417.

Indexed at, Google Scholar, Crossref

6. Saczkowski R, Dacey C, Bernier PL (2010) Does ABO-incompatible and ABO-compatible neonatal heart transplant have equivalent survival. Interact Cardiovasc Thorac Surg 10: 1026-1033.

Indexed at, Google Scholar, Crossref

7. Jeewa A, Manlhiot C, Kantor PF, Mital S, McCrindle BW, et al. (2014) Risk factors for mortality or delisting of patients from the pediatric heart transplant waiting list. J Thorac Cardiovasc Surg 147: 462-468.

Indexed at, Google Scholar, Crossref

8. Conway J, Manlhiot C, Kirk R, Edwards LB, McCrindle BW, et al. Mortality and morbidity after retransplantation after primary heart transplant in childhood: an analysis from the registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 33: 241-251.

Indexed at, Google Scholar, Crossref

9. R D Vanderlaan, C Manlhiot, L B Edwards, J Conway, B W McCrindle, et al. (2015) Risk factors for specific causes of death following pediatric heart transplant: An analysis of the registry of the International Society of Heart and Lung Transplantation. Pediatr Transplant 19: 896-905.

Indexed at, Google Scholar, Crossref

10. Sivathasan C, Lim CP, Kerk KL, Sim DK, Mehra MR, et al. (2017) Mechanical circulatory support and heart transplantation in the Asia Pacific region. J Heart Lung Transplant 36: 13-18.

Indexed at, Google Scholar, Crossref