Stepwise development and expansion of an abdominal normothermic regional perfusion program for donation after circulatory determination of death organ procurement.

INTRODUCTION: Normothermic regional perfusion (NRP) represents an innovative technology that improves the outcomes for liver and kidney recipients of donation after circulatory determination of death (DCD) organs but protocols for abdominal-only NRP (A-NRP) DCD are lacking in the US. METHODS: We describe the implementation and expansion strategies of a transplant-center-based A-NRP DCD program that has grown in volume, geographical reach, and donor acceptance parameters, presented as four eras. RESULTS: In the implementation era, two donors were attempted, and one liver graft was transplanted. In the local expansion era, 33% of attempted donors resulted in transplantation and 42% of liver grafts from donors who died within the functional warm ischemic time (fWIT) limit were transplanted. In the Regional Expansion era, 25% of attempted donors resulted in transplantation and 50% of liver grafts from donors who died within the fWIT limit were transplanted. In the Donor Acceptance Expansion era, 46% of attempted donors resulted in transplantation and 72% of liver grafts from donors who died within the fWIT limit were transplanted. Eight discarded grafts demonstrated a potential opportunity for utilization. CONCLUSION: The stepwise approach to building an A-NRP program described here can serve as a model for other transplant centers.

Procurement Trends, Indications, and Outcomes of Heart-Lung Transplantation in the Contemporary Era.

BACKGROUND: Evolving trends in organ procurement and technological innovation prompted an investigation into recent trends, indications, and outcomes following combined heart-lung transplantation (HLTx). METHODS: The United Network for Organ Sharing database was queried for all adult (≥18 years) HLTx performed between July 1, 2013 and June 30, 2023. Patients with previous transplants were excluded. The primary endpoint was the effect of donor, recipient, and transplantation characteristics on 1- and 5-year survival. Secondary analyses included a comparison of HLTx at high- and low-volume centers, an assessment of HLTx following donation after circulatory death (DCD), and an evaluation of HLTx volume over time. Cox proportional-hazards models were used to assess factors associated with mortality. Temporal trends were evaluated with linear regression. RESULTS: After exclusions, 319 patients were analyzed, of whom 5 (1.6%) were DCD. HLTx volume increased from 2013 to 2023 (p < 0.001). One- and 5-year survival following HLTx was 84.0% and 59.5%, respectively. One-year survival was higher for patients undergoing HLTx at a high-volume center (88.3% vs. 77.9%; p = 0.012). After risk adjustment, extracorporeal membrane oxygenation support 72 h posttransplant and predischarge dialysis were associated with increased 1-year mortality (HR = 3.19, 95% CI = 1.86-5.49 and HR = 3.47, 95% CI = 2.17-5.54, respectively) and 5-year mortality (HR = 2.901, 95% CI = 1.679-5.011 and HR = 3.327, 95% CI = 2.085-5.311, respectively), but HLTx at a high-volume center was not associated with either. CONCLUSIONS: HLTx volume has resurged, with DCD HLTx emerging as a viable procurement strategy. Factors associated with 1- and 5-year survival may be used to guide postoperative management following HLTx.

American Society of Transplant Surgeons recommendations on best practices in donation after circulatory death organ procurement.

The American Society of Transplant Surgeons supports efforts to increase the number of organs that are critically needed for patients desperately awaiting transplantation. In the United States, transplantation using organs procured from donation after circulatory death (DCD) donors has continued to increase in number. Despite these increases, substantial variability in the utilization and practices of DCD transplantation still exists. To improve DCD organ utilization, it is important to create a set of best practices for DCD recovery. The following recommendations aim to provide guidance on contemporary issues surrounding DCD organ procurement in the United States. A work group was composed of members of the American Society of Transplant Surgeon Scientific Studies Committee and the Thoracic Organ Transplantation Committee. The following topics were identified by the group either as controversial or lacking standardization: prewithdrawal preparation, definition of donor warm ischemia time, DCD surgical technique, combined thoracic and abdominal procurements, and normothermic regional perfusion. The proposed recommendations were classified on the basis of the grade of available evidence and the strength of the recommendation. This information should be valuable for transplant programs as well as for organ procurement organizations and donor hospitals as they develop robust DCD donor procurement protocols.

First case report of multivisceral transplant from a deceased cardiac death donor.

The current shortage of pediatric multivisceral donors accounts for the long time and mortality on the waiting list of pediatric patients. The use of donors after cardiac death, especially after the outbreak of normothermic regional perfusion, has increased in recent years for all solid organs except the intestine, mainly because of its higher susceptibility to ischemia-reperfusion injury. We present the first literature case of multivisceral donors after cardiac death transplantation in a 13-month-old recipient from a 2.5-month-old donor. Once exitus was certified, an extracorporeal membrane oxygenation circuit was established, cannulating the aorta and infrarenal vena cava, while the supra-aortic branches were clamped. The abdominal organs completely recovered from ischemia through normothermic regional perfusion (extracorporeal membrane oxygenation initially and beating heart later). After perfusion with the preservation solution, the multivisceral graft was uneventfully implanted. Two months later, the patient was discharged without any complications. This case demonstrates the possibility of reducing the time spent on the waiting list for these patients.

Heart-liver-kidney transplantation for AL amyloidosis using normothermic recovery and storage from a donor following circulatory death: Short-term outcome in a first-in-world experience.

AL amyloidosis is a rare condition characterized by the overproduction of an unstable free light chain, protein misfolding and aggregation, and extracellular deposition that can progress to multiorgan involvement and failure. To our knowledge, this is the first worldwide report to describe triple organ transplantation for AL amyloidosis and triple organ transplantation using thoracoabdominal normothermic regional perfusion recovery with a donation from a circulatory death (DCD) donor. The recipient was a 40-year-old man with multiorgan AL amyloidosis with a terminal prognosis without multiorgan transplantation. An appropriate DCD donor was selected for sequential heart, liver, and kidney transplants via our center's thoracoabdominal normothermic regional perfusion pathway. The liver was additionally placed on an ex vivo normothermic machine perfusion, and the kidney was maintained on hypothermic machine perfusion while awaiting implantation. The heart transplant was completed first (cold ischemic time [CIT]: 131 minutes), followed by the liver transplant (CIT: 87 minutes, normothermic machine perfusion: 301 minutes). Kidney transplantation was performed the following day (CIT: 1833 minutes). He is 8 months posttransplant without evidence of heart, liver, or kidney graft dysfunction or rejection. This case highlights the feasibility of normothermic recovery and storage modalities for DCD donors, which can expand transplant opportunities for allografts previously not considered for multiorgan transplantations.

Cerebral cortical activity after withdrawal of life-sustaining measures in critically ill patients.

Establishing when cerebral cortical activity stops relative to circulatory arrest during the dying process will enhance trust in donation after circulatory determination of death. We used continuous electroencephalography and arterial blood pressure monitoring prior to withdrawal of life sustaining measures and for 30 min following circulatory arrest to explore the temporal relationship between cessation of cerebral cortical activity and circulatory arrest. Qualitative and quantitative EEG analyses were completed. Among 140 screened patients, 52 were eligible, 15 were enrolled, 11 completed the full study, and 8 (3 female, median age 68 years) were included in the analysis. Across participants, EEG activity stopped at a median of 78 (Q1 = -387, Q3 = 111) seconds before circulatory arrest. Following withdrawal of life sustaining measures there was a progressive reduction in electroencephalographic amplitude (p = .002), spectral power (p = .008), and coherence (p = .003). Prospective recording of cerebral cortical activity in imminently dying patients is feasible. Our results from this small cohort suggest that cerebral cortical activity does not persist after circulatory arrest. Confirmation of these findings in a larger multicenter study are needed to help promote stakeholder trust in donation after circulatory determination of death.

Applying the ethical framework for donation after circulatory death to thoracic normothermic regional perfusion procedures.

The novel approach of thoracic normothermic regional perfusion (TA-NRP) for in-situ preservation of organs prior to removal presents a new series of ethical questions about donation after circulatory determination of death (DCD) procedures. This manuscript describes the framework used for the analysis of ethical acceptability of DCD donation and analyzes the specific practice of TA-NRP DCD within that framework to demonstrate that TA-NRP DCD can be performed within the ethical boundaries of DCD donation. We argue that TA-NRP DCD organ procurements meet the ethical standards of informed consent, non-maleficence, adherence to the dead donor rule, and irreversibility, and as such, are ethically acceptable. We also describe the potential benefits of TA-NRP DCD procedures that result from higher organ yields and better recipient outcomes. Finally, we call for open and transparent support of TA-NRP DCD by professional organizations as a necessary cornerstone for the advancement of TA-NRP DCD procedures.

The impact of machine perfusion of the heart on warm ischemia time and organ yield in donation after circulatory death.

Successful normothermic machine perfusion of heart allografts (MPH) has led to rapid growth in transplantation of donation after circulatory death (DCD) heart allografts but has introduced complexity in the procurement process. This study examines the impact of MPH use in DCD procurements on warm ischemia time (WIT) and organ yield. DCD procurements from 2019 to 2020 were identified using the OPTN database. Procurements with and without the use of MPH were compared using propensity score matching. Observed to expected (O:E) yield ratios were calculated, where the expected values were obtained using the models developed by the Scientific Registry of Transplant Recipients. In total, 1237 DCD procurements met inclusion criteria (MPH: 109 and control: 1128). After PSM, no difference was found between groups in median total WIT (24.0 min vs. 24.0 min, p = .89), but the MPH group demonstrated shorter median operative WIT (circulatory arrest to cross-clamp; 8.7 min vs. 10.9 min, p = .003). The overall organ yield of DCD heart donors was observed to be 33% higher than expected (O:E 1.33; 95% CI: 1.22-1.45). Observed yield of non-heart organs was not significantly different from expected for liver, kidney, lung, and pancreas grafts. MPH use in DCD procurements does not lead to delays in WIT and does not negatively affect organ yield of other concurrently procured organs.

Outcomes of lung transplantation from organ donation after medical assistance in dying: First North American experience.

Over 2.5% of deaths in Canada occur as a result from medical assisting in dying (MAID), and a subset of these deaths result in organ donation. However, detailed outcomes of lung transplant recipients using these donors is lacking. This is a retrospective single center cohort study comparing lung transplantation outcomes after donation using MAID donors compared to neurologically determined death and controlled donation after circulatory death (NDD/cDCD) donors from February 2018 to July 2021. Thirty-three patients received lungs from MAID donors, and 560 patients received lungs from NDD/cDCD donors. The donor diagnoses leading to MAID provision were degenerative neurological diseases (n = 33) and end stage organ failure (n = 5). MAID donors were significantly older than NDD/cDCD donors (56 [IQR 49-64] years vs. 48 [32-59]; p = .0009). Median ventilation period and 30 day mortality were not significantly different between MAID and NDD/cDCD lungs recipients (ventilation: 1 day [1-3] vs 2 days [1-3]; p = .37, deaths 0% [0/33] vs. 2% [11/560], p = .99 respectively). Intermediate-term outcomes were also similar. In summary, for lung transplantation using donors after MAID, recipient outcomes were excellent. Therefore, where this practice is permitted, donation after MAID should be strongly considered for lung transplantation as a way to respect donor wishes while substantially improving outcomes for recipients with end-stage lung disease.

Successful heart transplantation from donation after euthanasia with distant procurement using normothermic regional perfusion and cold storage.

While euthanasia has been legalized in a growing number of countries, organ donation after euthanasia is only performed in Belgium, the Netherlands, Spain, and Canada. Moreover, the clinical practice of heart donation after euthanasia has never been reported before. We describe the first case of a heart donated after euthanasia, reconditioned with thoraco-abdominal normothermic regional perfusion, preserved using cold storage while being transported to a neighboring transplant center, and then successfully transplanted following a procurement warm ischemic time of 17 min. Heart donation after euthanasia using thoraco-abdominal normothermic regional perfusion is feasible, it could expand the heart donor pool and reduce waiting lists in countries where organ donation after euthanasia can be performed.

Practice and challenges for organ donation after medical assistance in dying: A scoping review including the results of the first international roundtable in 2021.

The procedure combining medical assistance in dying (MAiD) with donations after circulatory determination of death (DCDD) is known as organ donation after euthanasia (ODE). The first international roundtable on ODE was held during the 2021 WONCA family medicine conference as part of a scoping review. It aimed to document practice and related issues to advise patients, professionals, and policymakers, aiding the development of responsible guidelines and helping to navigate the issues. This was achieved through literature searches and national and international stakeholder meetings. Up to 2021, ODE was performed 286 times in Canada, the Netherlands, Spain, and Belgium, including eight cases of ODE from home (ODEH). MAiD was provided 17,217 times (2020) in the eight countries where ODE is permitted. As of 2021, 837 patients (up to 14% of recipients of DCDD donors) had received organs from ODE. ODE raises some important ethical concerns involving patient autonomy, the link between the request for MAiD and the request to donate organs and the increased burden placed on seriously ill MAiD patients.

Inflammation in the early phase after kidney transplantation is associated with increased long-term all-cause mortality.

In the general population, low-grade inflammation has been established as a risk factor for all-cause mortality. We hypothesized that an inflammatory milieu beyond the time of recovery from the surgical trauma could be associated with increased long-term mortality in kidney transplant recipients (KTRs). This cohort study included 1044 KTRs. Median follow-up time post-engraftment was 10.3 years. Inflammation was assessed 10 weeks after transplantation by different composite inflammation scores based on 21 biomarkers. We constructed an overall inflammation score and five pathway-specific inflammation scores (fibrogenesis, vascular inflammation, metabolic inflammation, growth/angiogenesis, leukocyte activation). Mortality was assessed with Cox regression models adjusted for traditional risk factors. A total of 312 (29.9%) patients died during the follow-up period. The hazard ratio (HR) for death was 4.71 (95% CI: 2.85-7.81, p < .001) for patients in the highest quartile of the overall inflammation score and HRs 2.35-2.54 (95% CI: 1.40-3.96, 1.52-4.22, p = .001) for patients in the intermediate groups. The results were persistent when the score was analyzed as a continuous variable (HR 1.046, 95% CI: 1.033-1.056, p < .001). All pathway-specific analyses showed the same pattern with HRs ranging from 1.19 to 2.70. In conclusion, we found a strong and consistent association between low-grade systemic inflammation 10 weeks after kidney transplantation and long-term mortality.

Successful lung transplantation with graft recovered after thoracoabdominal normothermic perfusion from donor after circulatory death.

Lung transplantation with lungs procured from donors after circulatory death (DCD) has been established as an alternative technique to traditional donation after brain death (DBD) with comparable outcomes. Recently, in situ thoracoabdominal normothermic regional perfusion (TA-NRP) has emerged as a novel technique employed in the procurement of cardiac allografts after circulatory death. TA-NRP, in contrast to ex situ machine perfusion, has the advantage of allowing in situ assessment of donor organs prior to final acceptance. However, there are some concerns that this technique may adversely impact the quality of lung allografts. Here, we present a case of a successful bilateral sequential lung transplantation in a patient with postinflammatory pulmonary fibrosis due to acute respiratory distress syndrome (ARDS), with lungs procured after normothermic in situ lung perfusion. Apart from the lungs, heart, liver, and kidneys were also successfully transplanted from this donor.

Thromboelastography profiles for controlled circulatory death donors: Validating the role of heparin.

Controlled donation after circulatory death (cDCD) liver transplants are associated with increased ischemic-type biliary complications. Microvascular thrombosis secondary to decreased donor fibrinolysis may contribute to bile duct injury. We hypothesized that cDCD donors are hypercoagulable with impaired fibrinolysis and aim to use thromboelastography to characterize cDCD coagulation profiles.

Histological evaluation of ischemic alterations in donors after cardiac death: A useful tool to predict post-transplant renal function.

Kidneys retrieved from donors after cardiac death (DCD) pose significant challenges from a clinical and technical point of view, undergoing a variable degree of ischemia-reperfusion injury. At present, the utilization of kidneys is assessed according to the Karpinski score, which does not take into account the ischemic insult and does not predict the functional recovery of the organ once transplanted. Therefore, the correlation between biopsy results and post-transplant graft function is still debated. In this study we examined kidney biopsies from DCD donors; we calculated the Karpinski score and subsequently identified and quantified the ischemic lesions in the glomerular, interstitial, and tubular compartments. These same lesions were quantified in kidney biopsies from donors after brain death (DBD) in a case-control analysis. The collected data were correlated with the clinical data of the donors and the post-transplant follow-up. Proximal tubule alterations are crucial in ischemia-reperfusion damage, showing precise histological alterations, which are more frequent in DCD than in DBD donors and are statistically correlated with functional recovery of the organ. Quantification of ischemic tubular lesions in biopsies of kidneys from DCD donors is a useful tool for predicting post-transplant renal function and a valid parameter for assessing the quality of the graft.

Impact of donation after circulatory death donor allografts on outcomes following liver transplantation for fulminant hepatic failure in the United States.

Limited data exist regarding the impact of donation after circulatory death (DCD) allografts on outcomes following liver transplantation in fulminant hepatic failure (FHF). Utilizing the Scientific Registry of Transplant Recipients (SRTR), we compared outcomes after DCD in FHF to donation after brain death (DBD) in FHF and DCD in non-FHF over a 15-year period. Primary outcome measures were graft and patient survival. A total of 117, 3437, and 4379 recipients underwent DCD-FHF, DBD-FHF and DCD-non-FHF, respectively. One-year graft survival in DCD-FHF was inferior to DBD-FHF (72.9% vs. 83.8%, p = .002), but comparable to DCD-non-FHF (72.9% vs. 82.7%, p = .23). However, 3- and 5-year graft survival in DCD-FHF were comparable to DBD-FHF (67.9 vs. 77.6%, p = .63; 57.8% vs. 73.2%, p = .27) and DCD-non-FHF (67.9% vs. 72.9%, p = .44; 57.8% vs. 66.6%, p = .06). One-, 3-, and 5-year patient survival were also comparable among the three groups. Graft and patient survival in DCD-FHF improved over the study period. Multivariable analysis identified recipient age, male gender, African American ethnicity, donor age, and cold ischemia time as predictors of graft and patient survival in FHF, while DCD status was only predictive of graft survival. Long-term graft survival and patient survival in DCD-FHF are comparable to DBD-FHF and DCD-non-FHF. Consideration of DCD in FHF could help expand the donor pool in this subset of critically ill patients.

Optimal donation of kidney transplants after controlled circulatory death.

Controlled donation after circulatory death (cDCD) is used for "extended criteria" donors with poorer kidney transplant outcomes. The French cDCD program started in 2015 and is characterized by normothermic regional perfusion, hypothermic machine perfusion, and short cold ischemia time. We compared the outcomes of kidney transplantation from cDCD and brain-dead (DBD) donors, matching cDCD and DBD kidney transplants by propensity scoring for donor and recipient characteristics. The matching process retained 442 of 499 cDCD and 809 of 6185 DBD transplantations. The DGF rate was 20% in cDCD recipients compared with 28% in DBD recipients (adjusted relative risk [aRR], 1.43; 95% confidence interval [CI] 1.12-1.82). When DBD transplants were ranked by cold ischemia time and machine perfusion use and compared with cDCD transplants, the aRR of DGF was higher for DBD transplants without machine perfusion, regardless of the cold ischemia time (aRR with cold ischemia time <18 h, 1.57; 95% CI 1.20-2.03, vs aRR with cold ischemia time ≥18 h, 1.79; 95% CI 1.31-2.44). The 1-year graft survival rate was similar in both groups. Early outcome was better for kidney transplants from cDCD than from matched DBD transplants with this French protocol.

Outcomes after simultaneous pancreas-kidney transplantation from donation after circulatory death donors: A UK registry analysis.

There are concerns that simultaneous pancreas-kidney (SPK) transplants from donation after circulatory death (DCD) donors have a higher risk of graft failure than those from donation after brain death (DBD) donors. A UK registry analysis of SPK transplants between 2005 and 2018 was performed. Pancreas survivals of those receiving organs from DCD or DBD donors were compared. Multivariable analyses were used to adjust for baseline differences between the two groups and to identify factors associated with pancreas graft loss. A total of 2228 SPK transplants were implanted; 403 (18.1%) were from DCD donors. DCD donors were generally younger, slimmer, less likely to have stroke as a cause of death, with lower terminal creatinines and shorter pancreas cold ischemic times than DBD donors. Median (IQR) follow-up was 4.2 (1.6-8.1) years. On univariable analysis, there were no statistically significant differences in 5-year death-censored pancreas graft survival between the two donor types (79.5% versus 80.4%; p = .86). Multivariable analysis showed no statistically significant differences in 5-year pancreas graft loss between transplants from DCD (n = 343) and DBD (n = 1492) donors (hazard ratio 1.26, 95% CI 0.76-1.23; p = .12). The findings from this study support the increased use of SPK transplants from DCD donors.

Improved short-term outcomes of kidney transplants in controlled donation after the circulatory determination of death with the use of normothermic regional perfusion.

Normothermic regional perfusion (NRP) allows the in situ perfusion of organs with oxygenated blood in donation after the circulatory determination of death (DCDD). We aimed at evaluating the impact of NRP on the short-term outcomes of kidney transplants in controlled DCDD (cDCDD). This is a multicenter, nationwide, retrospective study comparing cDCDD kidneys obtained with NRP versus the standard rapid recovery (RR) technique. During 2012-2018, 2302 cDCDD adult kidney transplants were performed in Spain using NRP (n = 865) or RR (n = 1437). The study groups differed in donor and recipient age, warm, and cold ischemic time and use of ex situ machine perfusion. Transplants in the NRP group were more frequently performed in high-volume centers (≥90 transplants/year). Through matching by propensity score, two cohorts with a total of 770 patients were obtained. After the matching, no statistically significant differences were observed between the groups in terms of primary nonfunction (p = .261) and mortality at 1 year (p =  .111). However, the RR of kidneys was associated with a significantly increased odds of delayed graft function (OR 1.97 [95% CI 1.43-2.72]; p < .001) and 1-year graft loss (OR 1.77 [95% CI 1.01-3.17]; p = .034). In conclusion, compared with RR, NRP appears to improve the short-term outcomes of cDCDD kidney transplants.

Clinical use of donation after circulatory death pancreas for islet transplantation.

Due to a shortage of donation after brain death (DBD) organs, donation after circulatory death (DCD) is increasingly performed. In the field of islet transplantation, there is uncertainty regarding the suitability of DCD pancreas in terms of islet yield and function after islet isolation. The aim of this study was to investigate the potential use of DCD pancreas for islet transplantation. Islet isolation procedures from 126 category 3 DCD and 258 DBD pancreas were performed in a 9-year period. Islet yield after isolation was significantly lower for DCD compared to DBD pancreas (395 515 islet equivalents [IEQ] and 480 017 IEQ, respectively; p = .003). The decrease in IEQ during 2 days of culture was not different between the two groups. Warm ischemia time was not related to DCD islet yield. In vitro insulin secretion after a glucose challenge was similar between DCD and DBD islets. After islet transplantation, DCD islet graft recipients had similar graft function (AUC C-peptide) during mixed meal tolerance tests and Igls score compared to DBD graft recipients. In conclusion, DCD islets can be considered for clinical islet transplantation.