Normothermic regional perfusion (NRP) has emerged as one of the most consequential innovations in modern liver transplantation, particularly in the context of controlled donation after circulatory death (cDCD). Historically, cDCD liver grafts have been associated with inferior outcomes compared with donation after brain death (DBD), largely due to warm ischemia and subsequent ischemia-reperfusion injury. These insults translated clinically into higher rates of early allograft dysfunction (EAD), primary nonfunction (PNF), ischemic cholangiopathy, and non-anastomotic biliary strictures (NAS). The review by Imai and colleagues provides a comprehensive and timely synthesis of how NRP is altering this paradigm by addressing the biological consequences of warm ischemia at their source.
NRP involves restoring in situ, oxygenated, normothermic blood flow to donor organs after declaration of death, using extracorporeal circulation while maintaining safeguards against cerebral or coronary reperfusion. Two principal strategies are described: abdominal NRP (A-NRP), which perfuses abdominal organs only, and thoracoabdominal NRP (TA-NRP), which re-establishes cardiac activity and perfuses both thoracic and abdominal organs. Although initially developed in the early 2000s, NRP gained widespread adoption across Europe during the past decade and has more recently expanded in the United States following endorsement by professional societies.
The authors summarize robust clinical evidence demonstrating that NRP markedly improves outcomes compared with traditional super-rapid recovery (SRR) and static cold storage. Large multicenter retrospective studies from Spain and the United States consistently show lower rates of EAD, biliary complications, hepatic artery thrombosis, retransplantation, and graft loss with NRP-supported cDCD livers. Particularly striking is the reduction in non-anastomotic biliary strictures, which fall to single-digit percentages and in some series approach zero. These biliary benefits are critical, as ischemic cholangiopathy has historically been the Achilles’ heel of cDCD liver transplantation.
Meta-analyses reinforce these findings, reporting one-year graft survival exceeding 90% and NAS rates as low as 1–4% in NRP-supported cDCD grafts. Importantly, when cDCD livers recovered with NRP are compared directly with DBD grafts, outcomes are increasingly equivalent. Matched cohort studies from France and Spain demonstrate comparable rates of EAD, acute kidney injury, arterial complications, biliary complications, and both patient and graft survival. In some analyses, longer-term graft survival even favors the NRP-cDCD cohort, underscoring how effectively NRP mitigates warm ischemic injury.
Beyond comparisons with SRR and DBD, the review carefully evaluates NRP relative to other machine perfusion strategies, including normothermic machine perfusion (NMP) and hypothermic oxygenated perfusion (HOPE). While each modality confers benefits over static cold storage, current evidence suggests that NRP offers broader and more consistent improvements, particularly in biliary outcomes and early graft function. Several comparative studies indicate that only NRP significantly reduces clinically relevant NAS, while also lowering post-reperfusion syndrome, early kidney injury, and retransplantation rates. These advantages may reflect the physiologic completeness of in situ reperfusion, including restoration of the peribiliary vascular plexus before cold ischemia.
The review also highlights the emerging role of sequential perfusion strategies, in which ex situ machine perfusion is applied after NRP. Although meta-analyses suggest that the primary benefit derives from NRP itself, selective use of NMP or HOPE after NRP may be advantageous in marginal grafts, prolonged ischemia, or complex recipient scenarios. In such cases, ex situ perfusion can extend viability assessment, improve logistics, and provide additional reassurance for graft acceptance.
A major contribution of this article is its detailed discussion of viability assessment during NRP. The authors emphasize a multiparametric approach incorporating lactate kinetics, transaminase trends, macroscopic appearance, and, in some centers, histological evaluation. Declining lactate levels and stable or decreasing transaminases during NRP are repeatedly associated with favorable outcomes, although absolute thresholds vary across institutions. The lack of universal criteria underscores both the flexibility and the current limitation of NRP, highlighting the need for continued standardization as adoption expands.
Importantly, NRP is not only improving outcomes but also transforming donor utilization. National data from the United Kingdom and the United States demonstrate dramatic increases in liver utilization rates following routine NRP implementation, including safe transplantation of extended-criteria donors and elderly grafts that would previously have been declined. By expanding the effective donor pool while maintaining excellent outcomes, NRP directly addresses one of transplantation’s most pressing challenges: the persistent gap between organ supply and demand.
In conclusion, this review positions normothermic regional perfusion as a transformative platform in cDCD liver transplantation. The accumulated evidence shows that NRP consistently reduces biliary complications, improves graft function, and achieves outcomes comparable to DBD transplantation, while simultaneously expanding donor utilization. Although heterogeneity in protocols and assessment criteria remains, the trajectory is clear—NRP is redefining standards of viability and reshaping the future of liver transplantation worldwide.
