Meng et al described a 7-y single-center experience with ischemia-free liver transplantation (IFLT), assessing procedural implementation and clinical outcomes.1 The authors present a retrospective analysis of 144 donation-after-brain-death (DBD) liver transplants, of which approximately two-thirds met extended criteria donor definitions. After propensity score matching, outcomes of 72 IFLT grafts were compared with 72 grafts undergoing conventional procurement followed by normothermic machine perfusion (NMP). Perfusion durations were similar between groups (median 300 min for IFLT versus 270 min for NMP), and NMP grafts underwent a cold flush before and after perfusion without intervening cold storage. Six IFLT grafts (8.3%) exhibited macrovesicular steatosis (>40%). The primary study endpoint was early allograft dysfunction (EAD), and secondary outcomes included postoperative complications, comprehensive complication index, and 1-y posttransplant survival. The authors found a statistically significantly lower EAD rate with IFLT compared with NMP (15.30% versus 44.40%, P < 0.001). Additionally, in the IFLT group, the 1-y comprehensive complication index was lower (P = 0.039), and 1-y survival was higher (log-rank P = 0.0084). This study advances efforts to redefine ischemia in transplantation. Practical constraints will determine IFLT’s clinical role. Since its first description in 2018, the Renji program progressed from animal feasibility to a randomized clinical trial and mechanistic validation studies (Figure 1). The notion of eliminating ischemia–reperfusion injury (IRI) is undoubtedly compelling, as it is the leading cause of graft dysfunction after liver transplantation. Yet, the technique’s inherent constraints: donor type, perfusion time, and logistical requirements, may confound the interpretation of its benefits. Observed benefits may reflect biological protection from ischemia elimination and enhanced logistics inherent to the IFLT workflow. Clarifying whether ischemia elimination per se, rather than concurrent procedural factors, drives the observed outcomes remains a key question.FIGURE 1.: Development of the IFLT concept from initial animal studies to clinical evaluation. Timeline includes key milestones reported by the Renji program, including proof-of-concept, perfusion-characterization, randomized trials, mechanistic studies, and the recent 7-y cohort. N represents the number of cases that underwent the IFLT technique in the published study. 1 IFLT, ischemia-free liver transplantation.In IFLT, the donor hepatic artery, portal vein, and infra-hepatic vena cava are cannulated in situ before cross-clamp and hepatectomy, allowing continuous NMP from procurement through implantation. By maintaining uninterrupted normothermic oxygenated flow from procurement through implantation, IFLT replaces cold flush and static cold storage with NMP thereby reducing IRI with a seamless perfusion transition, limiting succinate buildup and downstream inflammatory injury.2 Operationally, it requires a dedicated perfusion circuit, real-time monitoring, and tight synchronization between donor and recipient surgery teams. These demands limit reproducibility outside highly specialized centers. Next, the original IFLT-approach remains limited to brain-death donors (DBD) given the requirement for uninterrupted in situ and ex situ oxygenation and perfusion. Reported IFLT-treatments are typically shorter than other NMP protocols (<4 h). Early IFLT procedures were performed using a commercial dual-pump normothermic perfusion system (Liver Assist, XVIVO), though the program has since reported a transition to a custom in-house circuit currently entering clinical evaluation.1 Avoiding cold ischemia could redefine donor organ utilization. IFLT has consistently shown reduced EAD rates, lower transaminase peaks, and fewer biliary complications compared with conventional cold-stored grafts.1,3 By maintaining metabolic continuity, IFLT preserves mitochondrial integrity, potentially reducing postoperative biliary complications and the systemic inflammatory and innate response. Omics data show near-physiologic metabolic profiles under IFLT, yet transcriptional shifts begin with liver explantation from the donor itself, indicating surgical manipulation perturbs biology even when ischemia is avoided. This suggests that graft injury may begin with the act of procurement itself, independent of ischemic duration. Beyond graft outcomes, broader adoption could expand the donor pool by enabling use of extended criteria donor livers previously deemed risky for static cold storage. Standardized assessment of graft ischemia tolerance does not yet exist; metabolic profiling could enable targeted IFLT use. Despite such benefits, the barriers to implementation remain substantial. The concept of IFLT demands simultaneous availability of perfusion equipment, skilled operators, and surgical teams for both donor and recipient. Its reliance on in-hospital brain-death donors limits geographic flexibility and the application in donor after circulatory death donors where donor warm ischemia time always contributes to the overall injury. Next, prolonged NMP durations require very advanced perfusion systems and have been clinically applied in only 1 transplant case.4 Moreover, comparison studies on outcomes after living donor liver transplantation and IFLT have not yet been published. Comparable results may be achievable under IFLT-like conditions, such as donor-recipient proximity (in-house) and minimal preservation time, making it difficult to disentangle the benefits of “complete” ischemia avoidance from those of optimized logistics. Until multicenter trials replicate these results in broader settings, IFLT will remain an impressive but resource-intensive concept largely confined to a few pioneering programs. A custom portable circuit may broaden access, but feasibility must be balanced against stability and cost. Even in expert settings, sustaining long, stable normothermic perfusion is demanding; experimental reports of 14- to 17-d ex situ runs underscore the circuit complexity required.4,5 These experiences highlight that even with improved portability, reproducing stable, prolonged NMP for clinical IFLT remains a formidable logistical and physiological challenge. To translate IFLT into wider clinical practice, we need to identify which grafts truly benefit from ischemia avoidance. Biomarker-based donor profiling, for example, mitochondrial flavin mononucleotide release, succinate, or early dynamic injury signals, could stratify ischemia tolerance before donation surgery and organ preservation begins. Critically, we still do not know which livers, and why, fail to tolerate cooling and subsequent re-oxygenation, nor how best to reassess this vulnerability in clinical pathways. Embedding rapid assays (flavin mononucleotide/succinate), bedside risk scores (donor comorbidity, steatosis, hemodynamics), and early intraoperative readouts into donor-recipient matching could guide selection of IFLT versus other perfusion techniques including NMP and hypothermic oxygenated perfusion or hybrids. With improved upfront profiling, simplified circuits and coordinated logistics may become scalable; multicenter studies should validate safety and cost-effectiveness. In summary, Meng et al provide compelling evidence that IFLT can yield superior outcomes in different types of DBD liver transplantations. The challenge ahead is to define when, where, and for whom this complex strategy confers true advantage. As technology evolves, continuous perfusion may redefine organ preservation by rendering ischemia a controllable variable.
Fernandes et al. (Fri,) studied this question.