ECMO-Assisted In-Situ Normothermic Perfusion for Donation After Circulatory Determination of Death Kidney Transplantation: A Narrative Review

Introduction

Kidney transplantation using grafts from donors after neurological determination of death (DNDD; formerly DBD, donors after brain death) is a well-established treatment method for patients with end-stage renal disease. To meet the increasing demand for kidney grafts nationwide and worldwide, great efforts have been made to optimize graft allocation and extend the pool of suitable donors. Aside from using expanded criteria donors, one of the most common methods to increase the number of available kidney grafts is donation from donors after circulatory determination of death (DCDD; formerly DCD, donors after circulatory death). Grafts from DCDD are generally regarded as higher risk as they are more vulnerable to oxidative stress imposed by ischemic reperfusion injury [1[. The risk is not only a result of the donor’s physiological strain but is also exacerbated by graft harvesting and subsequent transplantation.

In 2023, 25.0% of all kidney transplants worldwide were performed using DCDD grafts [2], a significant increase from previous reports of 13.9% in 2021 [3]. Even though it is possible to gather grafts even in an uncontrolled scenario (uDCDD) based on the original Maastricht criteria (groups I and II, and possibly IV) [4], a controlled donation (cDCDD, Maastricht III) after purposely withdrawing life-sustaining treatment (WLST) is performed most frequently and yields results comparable to DNDD kidney transplantation [5]. DCDD grafts are usually harvested using the rapid recovery technique (declaration of death followed by rapid laparotomy with abdominal aorta cannulation and in-situ cold perfusion by a preservation solution cooled to about 4 °C). To further improve the results of cDCDD, kidney preservation using in-situ normothermic regional perfusion (NRP) by means of extracorporeal membrane oxygenation (ECMO) has been proposed. Some European countries (France, Italy, Spain, Belgium, Norway, Switzerland, and the United Kingdom) have already incorporated ECMO-based regional perfusion in their cDCDD transplantation regimens [6]. Unfortunately, this modification of DCDD transplantation highlights some technical, technological, and ethical considerations that need to be addressed at the institutional and national levels. Furthermore, the effect of ECMO NRP (nECMO or abdominal normothermic oxygenated recirculation) on graft and patient survival has not been thoroughly studied. In this review, we aim to summarize currently available knowledge on cDCDD with nECMO to provide information for nECMO integration into transplantation practice.

A narrative review of literature available until March 2025 was performed by searching PubMed/MEDLINE using the following search terms: “kidney” [Title/Abstract] AND (“transplantation” [Title/Abstract] OR “transplant” [Title/Abstract]) AND (“extracorporeal membrane oxygenation” [Title/Abstract] OR “ECMO” [Title/Abstract] OR “regional perfusion” [Title/Abstract]). This search yielded 282 results. Furthermore, the 2 most recent reports from the Global Observatory on Donation and Transplantation were added. By screening article abstracts, a total of 58 studies were included for full-text analysis. Further references were gathered by cross-referencing. After selection based on exclusion criteria, 26 articles and reports were included in the final review. The literature selection flowchart, including exclusion criteria, is shown in Figure 1.

Status of Implementation, Ethical Considerations

The European Committee on Organ Transplantation has published an updated overview of cDCDD adopters in the European region [6]. NRP during cDCDD shares most ethical considerations with regular DCDD transplants. First and foremost, it remains unclear whether it is ethical to perform specific interventions before the declaration of death, both before WLST and during the agonal period before blood circulation ceases. The ethical reasoning behind allowing premortem interventions is that when the potential donor agrees with organ donation (either due to being listed in an organ donor registry or due to a presumed consent with organ donation) and the treatment is futile, the main goal should be to preserve organs as much as possible to improve their outcomes after harvesting and transplantation. Furthermore, the agonal period brings blood circulation to a halt, which can prevent proper ECMO startup and heparin administration. It can therefore be assumed that pre-mortem cannulation and introduction of ECMO-supported regional perfusion would be beneficial for graft preservation and its outcomes.

Acceptance of drug administration or vessel cannulation ante mortem varies among individual nations. In the European region, only Austria, Belgium, France, Italy, Norway, Spain, and Switzerland accept interventions before the declaration of death. Apart from the United Kingdom, this overlaps with the regional usage of NRP during cDCDD [6]. Adding to the complexity, certain countries allow only vessel identification, while others allow full cannulation of the donor before the formal declaration of death. Even in cannulated donors, a balloon-assisted occlusion of the aorta is sometimes performed (usually based on local protocols), intending to prevent subsequent reperfusion of the heart and brain, further emphasizing the regional nature of such perfusion in contrast to perfusion of the whole body. These factors limit cross-study comparability. The cost of nECMO kidney perfusion is commonly deemed higher than that of in-situ cold perfusion [7]. However, it is possible that improved graft outcomes could lower the cost of recipient follow-up and dialysis. We found no published comparison of cost-effectiveness in the currently available literature.

Algorithms

Although there are no strict inclusion criteria for DCDD, commonly, patients with progressive refractory shock with organ failure or with end-stage cardiovascular disease are considered for donation. Some authors consider additional criteria, such as age younger than 55 years or the presence of severe neurological injury [8]. In an uncontrolled setting, usually a witnessed cardiac arrest with no-flow period of 15 to 30 minutes is required to consider uDCDD transplant. Due to the nature of cardiac arrest and resuscitation and its effect on organ perfusion, usually only grafts from patients without a history of cardiovascular disease or cancer are considered. Furthermore, it is mandatory to draw blood samples for complex assessment of the potential donor [7,9], especially serologic tests for HIV, hepatitis B, and hepatitis C infection. The decision to WLST should be made by a multidisciplinary team led by the treating physician and informed, whenever possible, by objective, evidence-based criteria. These can include validated scales or scoring systems, such as the European Resuscitation Council and European Society of Intensive Care Medicine algorithm [10] and the Corticosteroid Randomisation After Significant Head Injury (CRASH) model [11], among others [5]. It is generally recommended that the whole transplantation procedure be performed by a different team, excluding the primary caregiver. The decision should also be supported by communication with the patient or the patient’s surrogates. After WLST, the donor warm ischemia time (WIT) begins. The functional WIT starts when systolic arterial pressure drops under 60 mmHg or peripheral blood oxygen saturation (SpO2) drops below 80%. In the aforementioned countries, it is also possible to introduce ECMO cannulas before WLST, potentially reducing functional WIT to zero. In other countries or an uncontrolled setting, a cardiac arrest is expected sometime after WLST and needs to be verified by a combination of objective measures, such as absence of arterial pulsations, echocardiography, and electrocardiography. The time between WLST and the declaration of circulatory death is referred to as an agonal period. Based on available studies, 5 minutes of a no-touch period is sufficient to rule out spontaneous return of circulation [12]. After the no-touch period, it is possible to commence vessel cannulation. Commonly, the femoral artery and vein are cannulated unilaterally using the Seldinger technique under ultrasonographic guidance; it is also possible to introduce the arterial and venous line on opposite sides. After successful cannulation, an aortic occlusion balloon is commonly introduced and inflated in the descending thoracic aorta (just above the diaphragm), and the nECMO is started. Open or balloon-assisted occlusion of femoral vessels can also be used. Immediately after starting perfusion, heparin sulfate is applied into the circuit (3 mg/kg, followed by 1.5 mg/kg after every 90 minutes) [9], and its activity monitored by activated partial thromboplastin time or anti-Xa assay. Anticoagulation therapy can also be directed by activated clotting time, with a target of greater than 500 seconds [13]. In standard nECMO, blood temperature is kept in physiological range (37.0±0.5°C), pH is kept over 7.1, and PaCO2 is 30 to 50 mmHg [13]. At this point, perfusion of the kidneys with oxygenated blood is established. It is now possible to complete the donor examination – although in some protocols this period is arbitrarily limited to 240 minutes to minimize the effects of circulating cytokines and metabolites – and then transport the donor to the operating room. There, the abdomen is explored to rule out organ non-perfusion or existing malignancy, and perfusion is switched to a cooling solution using the same cannulas, similar to standard in-situ cold perfusion. Using this method, kidney grafts can be harvested, while limiting WIT to a bare minimum.

Graft Function, Morbidity, and Mortality

Generally, there is a lack of robust data on the efficacy of nECMO in comparison to in-situ cold perfusion with in-situ cold perfusion or total body cooling techniques. The general use of in-situ NRP may improve the immediate function of DCDD kidney grafts, lower the incidence of DGF or primary non-function in comparison with in-situ cold perfusion or total body cooling [14,15]. Results suggest that nECMO-DCDD transplants are comparable to regular DNDD kidney transplants in terms of DGF (5.3–43.0%), primary non-function (0.0% 6.0%), acute rejection (0.0–9.4%), and 1-year mortality (0.0–1.3%) [8,9,13,16–20]. The survival of patients using nECMO is not different when comparing NRP, in-situ cold perfusion, and DNDD transplantation regimens. In a study by Altshuler et al, when assessing donors connected to venoarterial or venovenous ECMO for non-donation purposes, grafts show similar rates of DGF and comparable renal function. Presence of venovenous ECMO increases the risk of graft discard more than 2-fold, which was not seen in venoarterial ECMO [21]. Even though this study did not use ECMO for NRP during kidney harvesting, we can extrapolate that preexisting cannulation in venoarterial ECMO patients may not significantly interfere with graft functions even during nECMO, and with ECMO already in place, a conversion to NRP would shorten WIT by a significant margin. Further research on this topic is, however, necessary. ECMO may also prove useful in the setting of hemodynamically unstable DNDD donors, which could be cannulated to stabilize circulation and regionally perfused in a controlled manner [22–24]. Notably, the kidney discard rates were similar in nECMO and regular DNDD transplantation.

Even in uDCDD, in which the metabolic consequences of unavoidable hypoperfusion are more pronounced [25], using nECMO greatly improves graft outcomes, which are then comparable to DNDD grafts. Molina et al showed that there is no difference in primary non-function between the 2 groups (6.4% for uDCDD vs 1.4% for DNDD, P=0.226). However, it needs to be noted that nECMO-uDCDD features statistically higher DGF incidence of 73.4% vs 46.4% (P<0.001). The incidence of DGF correlates closely with WIT [26]. This may be the reason to pursue the possibility of ECMO cannulation even before the declaration of death, which limits the WIT to a minimum. The onset of function was generally longer in uDCDD; however, 6 months after transplantation, no difference in estimated glomerular filtration rate (eGFR) was found. NRP also shortened the time to diuresis and improved creatinine clearance in the short term [9]. Wound dehiscence was also more frequent (13.9% vs 5.5%, P=0.002) in nECMO-uDCDD than in DNDD. In terms of mortality, NRP during uDCDD does not differ from DBDD at 5-year and 10-year checkpoints [27]. The summary of data from available studies is presented in Table 1.

Limitations of This Study

The narrative approach of this study limits the validity of described results. Higher quality synthetic or randomized studies would provide more robust data; however, due to differences in transplantation protocols across the world, the design and construction of studies included in this review vary significantly. In contrast to graft survival, patient overall survival is omitted in most studies, limiting the ability of this review to evaluate patient survival.

Conclusions

The use of nECMO in controlled and uncontrolled DCDD settings results in faster graft function onset and higher survival rates, comparable to DNDD transplants. Early ECMO cannulation minimizes WIT, enhancing graft function, although ethical and procedural constraints limit its widespread adoption. Future research should focus on randomized trials to better define the role of nECMO in transplantation protocols. These findings underscore the potential of nECMO to expand the donor pool and improve transplant outcomes, provided that ethical considerations are carefully managed.