Article
What’s past is prologue
W. Shakespeare – The Tempest, Act II, Scene I
Machine perfusion (MP) refers to the ex situ preservation of transplantable organs through the active circulation of a perfusion solution, under hypothermic or normothermic conditions. The history of MP dates back to the pioneering era of kidney and liver transplantation 1. Owing to its complexity and logistical burden, MP was soon abandoned following the introduction of preservation solutions for static cold storage (SCS). Interest in MP was revived in the early 2010s, particularly for the preservation of extended-criteria organs from donation after brain death (DBD) and in the setting of donation after circulatory death (DCD).
In 2009, Moers et al. demonstrated in a randomized controlled trial that hypothermic machine perfusion (HMP) of kidneys reduced the incidence of delayed graft function and improved graft survival 2. The first clinical application of hypothermic MP in liver transplantation in the modern era was reported in 2010 in the United States 3. Since then, the Zurich group proposed the hypothermic oxygenated perfusion (HOPE) protocol, which has proven effective in improving post-transplant outcomes, reducing biliary complications, and extending preservation times 4. These benefits have subsequently been confirmed by multiple randomized controlled trials conducted across Europe 5. In parallel, normothermic machine perfusion (NMP), by enabling ex situ viability assessment, has been shown to increase organ utilization and allow markedly prolonged preservation 6.
Since 2007, the Barcelona group has reported the use of normothermic regional perfusion (NRP) in uncontrolled DCD 7. This technique involves in situ reperfusion confined to the abdominal compartment, with the goal of preserving and restoring the function of the liver and the kidneys. However, early concerns about the potential impact on cerebral circulation initially hindered its broader adoption, particularly in other countries and in the United States.
In Italy, the evolution has followed a distinct path. According to Italian legislation, the declaration of death based on circulatory criteria requires a stand-off period of at least 20 minutes. This prolonged warm ischemia time, compared with other European countries and the United States, has historically limited the adoption of DCD transplantation. The first DCD in Italy occurred in Pisa in 2005, resulting in an unsuccessful liver transplant. In 2007, the “Programma Alba” (Sunrise Program) was initiated in Pavia, with a protocol that included the use of normothermic regional perfusion (NRP) for the management of uncontrolled DCD donors (Maastricht type II). This program marked the beginning of a successful experience, although initially limited to a small number of cases 8.
The first successful DCD liver transplant in Italy was procured in Pavia using NRP and transplanted at Niguarda Hospital in September 2015 9. The favourable outcome of this procedure led to the development of a dedicated DCD liver transplant program at Niguarda, initially based on uncontrolled donors from the Programma Alba in Pavia and from the extracorporeal life support (ECLS) program at San Raffaele Hospital in Milan 10.
Uncontrolled DCD posed significant logistical challenges, as procurement could occur at any time and required tight coordination between donor and recipient centres. NRP alone did not provide sufficient time for optimal organ management, particularly in uncontrolled donors, in whom progressive vasoplegia may limit the duration of effective perfusion. To address these limitations, from the third case onward, a sequential approach combining NRP in the donor with back-to-base HOPE prior to implantation was introduced 11. Although the initial rationale for adding HOPE was primarily logistical (i.e., allowing prolonged and controlled preservation) it also provided additional biological benefits. HOPE acted as a second-step reconditioning strategy following NRP, promoting mitochondrial recovery, restoration of energy stores, and mitigation of ischemia–reperfusion injury. This combined approach resulted in excellent clinical outcomes, with low rates of primary non-function and ischemic cholangiopathy despite the high-risk donor profile 7.
The expansion of DCD liver transplantation was paralleled by a rise in DCD kidney transplantation, frequently incorporating sequential hypothermic machine perfusion. The Bologna group reported favourable outcomes with DCD kidneys using a protocol analogous to that adopted for the liver, combining sequential NRP and HOPE 12.
In 2014, a successful DCD lung procurement had been performed at San Gerardo Hospital (Monza) and transplanted at Policlinico Hospital (Milan), using a protocol based only on donor lung ventilation followed by ex situ lung perfusion (EVLP) for assessment 13.
This approach subsequently gained wider adoption for isolated lung procurement, particularly in centres without ECLS availability. As DCD liver and kidney transplantation with NRP continued to expand, an integrated protocol was developed to avoid competition between thoracic and abdominal recovery strategies in centres equipped with ECLS 14. These allowed simultaneous recovery of lungs, liver, kidneys, and potentially pancreas (for islet transplantation), combining selective lung ventilation with abdominal NRP. In this setting, NRP was maintained during thoracic organ procurement and discontinued thereafter, following the reconditioning and functional assessment of the liver and kidneys.
Other Italian groups have reported favourable outcomes using sequential NMP in DCD liver transplantation, particularly in cases of NRP failure or inconclusive functional assessment. In such scenarios, NMP has proven effective in refining viability assessment and increasing safe liver utilization. As a result, an evolution of the original sequential protocol has been proposed: NRP is considered mandatory for abdominal DCD procurement; HOPE is applied to grafts meeting predefined criteria during NRP, whereas grafts not meeting these criteria undergo additional evaluation with NMP 15,16.
The first controlled DCD in Italy, following withdrawal of life-sustaining treatment, was performed in 2016 at San Giovanni Bosco Hospital (Turin), with the liver subsequently transplanted at Niguarda Hospital (Milan) and the kidneys at Policlinico San Matteo in Pavia 17. This milestone contributed to the progressive expansion of controlled DCD donation in Italy, which has since surpassed uncontrolled DCD activity. DCD transplantation is now an increasingly standardized practice in Italy. Excellent outcomes have been reported, including high mid- and long-term graft survival 18,19.
These results have raised questions regarding the incremental benefit of additional MP following NRP in selected cases, such as local donors with optimal NRP management and minimal cold ischemia time. Some centres have reported satisfactory outcomes using NRP alone in highly selected settings. However, these experiences are based on limited series and involve markedly different donor risk profiles. The relative contribution of NRP and subsequent MP (either HOPE or NMP) to graft reconditioning in sequential protocols remains to be fully elucidated. Nonetheless, the logistical advantages of extended preservation and enhanced graft assessment provided by MP represent a clear added value.
In May 2023, a DCD heart transplant was performed by the Padua team using thoraco-abdominal NRP 20. This technique enables the conversion of a DCD donor into a complete multiorgan donor, allowing the procurement of heart, lungs, liver, kidneys, and potentially the pancreas. The use of MP for cardiac preservation has also been proposed in this context.
Although DCD transplantation has been the primary driver of MP implementation in Italy, the use of this technology has progressively expanded to marginal DBD grafts and to logistical applications in both standard and extended-criteria organs. Some centres are currently exploring recipient-driven indications for MP, including complex recipients or retransplantation.
In 2017, the Niguarda group demonstrate the feasibility of preserving a liver for up to 20 hours using a combination of SCS and back-to-base HOPE for logistical purposes 21. A recent national analysis of prolonged HOPE cases has confirmed excellent outcomes 22. In addition, Niguarda was among the first Italian centres to adopt a delayed combined liver-kidney transplantation strategy, originally proposed by the Indianapolis group 23. Immediately after liver transplantation, conditions for kidney implantation are often suboptimal mainly due to hemodynamic instability. This protocol allows kidney transplantation to be safely delayed by 48-72 hours after liver reperfusion, with the kidney maintained on hypothermic MP. In line with this approach, several Italian centres now routinely preserve kidneys on MP, allowing transplantation to be safely rescheduled when required by clinical or logistical constraints.
In conclusion, the history of MP follows a broad historical trajectory: initially explored in the early era of transplantation, subsequently abandoned in favour of SCS, and reintroduced in the modern period. The Italian experience with MP has developed along a distinctive, integrated pathway shaped by regulatory constraints and clinical innovation, in which NRP has become the cornerstone of DCD abdominal organ recovery and is effectively combined with sequential strategies incorporating HOPE and, when indicated, NMP. This approach has enabled the safe expansion of DCD transplantation despite prolonged warm ischemia times, yielding excellent outcomes even with high-risk donors while improving logistical flexibility. At the same time, MP has progressively extended beyond DCD to include marginal and standard DBD grafts, as well as purely logistical indications. Although the relative contribution of each modality within sequential protocols remains to be fully defined, their combined use has clearly enhanced both graft preservation and utilization, and the Italian model, based on the pragmatic integration of complementary technologies, represents a robust framework for future developments in organ preservation.
Conflict of interest statement
The authors declare no conflict of interest.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethical consideration
Not applicable.
History
Received: May 2, 2026
Accepted: May 2, 2026
