Synergistic Ischemic Injury in DCD Kidney Transplantation: Rethinking Warm and Cold Ischemia as Interdependent Determinants of Graft Outcomes

Donation after circulatory death (DCD) kidney transplantation has become an increasingly important strategy to expand the donor pool.1 Despite many improvements in organ preservation and allocation systems, DCD grafts continue to remain susceptible to ischemia-reperfusion injury because of unavoidable and sequential warm and CITs. Although donor warm ischemia time (dWIT) and cold ischemia time (CIT) have previously been considered independent risk factors for early and late graft outcomes, recent evidence suggests that warm and cold ischemic injuries in DCD transplantation should be considered a sequential and additive pathological processes. While prolonged CIT has consistently been associated with delayed graft function (DGF) and reduced graft survival, its biological impact appears to depend strongly on the degree of preceding warm ischemic injury.2 We know that warm ischemia induces mitochondrial dysfunction, endothelial activation, ATP depletion, and a series of inflammatory cascades, which are the underpinning mechanisms behind organ injury. When followed by a prolonged cold ischemic period, these initiated mechanisms exaggerate the susceptibility of the graft to further damage, resulting in impairment of graft function. This “two-hit” model of injury represents a critical conceptual shift in the transplant era: ischemia is not simply a function of time, but a function of biological state at the time of preservation. Nakayama et al2 have provided a comprehensive study addressing and strongly supporting the “two-hit” ischemia model and highlight the importance of CIT on grafts experiencing longer dWIT and is highly valuable for reminding us of the fundamental limitations of DCD transplants. In grafts exposed to minimal warm ischemia, prolonged CIT may be partially tolerated. In contrast, in grafts with extended dWIT, prolonged CIT may result in significantly worse outcomes, including higher rates of DGF and inferior long-term graft survival. Large registry analyses have demonstrated that prolonged dWIT is independently associated with both early and late graft dysfunction, including reduced long-term survival.2,3 Similarly, other cohort studies have confirmed that dWIT is not only a determinant of early graft dysfunction but also a predictor of chronic graft failure, reinforcing its role as a central upstream determinant of transplant outcomes. The biological mechanisms underlying this interaction are increasingly being elucidated. Warm ischemia induces mitochondrial injury, oxidative stress, and endothelial dysfunction, creating a state of metabolic vulnerability. This “primed” state renders the graft highly susceptible to cold-induced metabolic suppression and reperfusion injury. More recently, ferroptosis has emerged as a key regulated cell death pathway in renal ischemia-reperfusion injury. Evidence suggests that warm ischemia may act as a critical trigger for ferroptosis, while cold ischemia exacerbates its downstream effects, thereby providing a mechanistic basis for synergistic injury.4 This evolving understanding has significant clinical implications. First, it necessitates a reevaluation of how CIT is interpreted in clinical decision-making. Rather than treating CIT as a universal risk factor, it should be considered within the context of donor-specific injury burden. Preservation outcomes are highly dependent on donor characteristics and that CIT thresholds vary significantly depending on donor type and graft quality. Second, donor warm ischemia time should be recognized as a primary determinant of graft vulnerability, rather than a secondary procurement variable. More recently, we are more attuned to the functional WIT that DCD organs are subjected to, as prolonged fWIT seems to be associated with an increased risk of primary nonfunction and therefore, associated with an increased risk of graft discards.1 Law et al5 have emphasized the importance of functional warm ischemia time as a more physiologically relevant metric than conventional time-based definitions. This reflects a broader shift toward physiological rather than purely chronological assessment of organ injury. These insights have direct implications for organ allocation and preservation strategies. Current allocation systems largely prioritize logistical considerations such as geographic proximity and waiting time. However, an ischemia-aware allocation model that integrates both dWIT and CIT could enable more precise risk stratification. For example, kidneys exposed to prolonged dWIT should be preferentially allocated to nearby centers to minimize additional cold ischemic exposure, whereas lower-risk grafts may tolerate extended transport times. Also, advances in preservation technologies offer promising advantages to overcome synergistic ischemic injury. Hypothermic machine perfusion has already demonstrated superiority over static cold storage in reducing DGF and improving early outcomes, especially in DCD grafts.6 However, its protective capacity appears limited in high-risk grafts with combined extended warm and cold ischemic injury. This has led to increasing interest in oxygenated perfusion strategies such as hypothermic oxygenated perfusion, which may better preserve mitochondrial integrity and reduce reperfusion injury. It should be remembered that while hypoxia is harmful, improper oxygenation can also increase reactive oxygen species levels, which could be detrimental to the graft. More advanced approaches, including normothermic regional perfusion (NRP), represent a further evolution in DCD organ management. De Beule et al7 demonstrated that NRP significantly improves graft outcomes in DCD transplantation by restoring physiological conditions before preservation, effectively reversing some of the harmful effects of warm ischemia. In addition to NRP, normothermic machine perfusion may also help to decrease early graft dysfunction and organ discard rates while future integration of biomarkers and artificial intelligence-assisted perfusion analytics could significantly transform organ preservation and selection strategies.8,9 Beyond perfusion techniques, there is a growing body of work suggesting that exogenous delivery of antioxidants, antiferroptotic agents, and mitochondrial stabilizers provide a paradigm shift that organ preservation is evolving toward active reconditioning, where metabolic, inflammatory, and endothelial dysfunctions can be modified ex vivo before transplantation.10 Therefore, it would not be unforeseeable to see a future where potential strategies such as incorporating NRP, normothermic machine perfusion, hypothermic oxygenated perfusion, and organ preservation supplementation working in concert to provide tailored protection and repair, especially for more marginal grafts. In conclusion, the recent report by Nakayama strongly supports reassessment of ischemia in DCD kidney transplantation. Donor warm and CITs should be accepted as interdependent determinants of graft injury. The concept of a “two-hit” synergistic ischemic injury provides a more accurate framework for understanding graft dysfunction and shows the limitations of current time-based risk models. Future progress in the field will depend on integrating ischemia-aware allocation strategies with advanced perfusion technologies and emerging reconditioning approaches.