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Normothermic machine perfusion for the assessment and transplantation of declined human kidneys from donation after circulatory death donors.

ABSTRACT: BACKGROUND:A significant proportion of donation after circulatory death (DCD) kidneys are declined for transplantation because of concerns over their quality. Ex vivo normothermic machine perfusion (NMP) provides a unique opportunity to assess the quality of a kidney and determine its suitability for transplantation. METHODS:In phase 1 of this study, declined human DCD kidneys underwent NMP assessment for 60 min. Kidneys were graded 1-5 using a quality assessment score (QAS) based on macroscopic perfusion, renal blood flow and urine output during NMP. In phase 2 of the study, declined DCD kidneys were assessed by NMP with an intention to transplant them. RESULTS:In phase 1, 18 of 42 DCD kidneys were declined owing to poor in situ perfusion. After NMP, 28 kidneys had a QAS of 1-3, and were considered suitable for transplantation. In phase 2, ten of 55 declined DCD kidneys underwent assessment by NMP. Eight kidneys had been declined because of poor in situ flushing in the donor and five of these were transplanted successfully. Four of the five kidneys had initial graft function. CONCLUSION:NMP technology can be used to increase the number of DCD kidney transplants by assessing their quality before transplantation.

SUBMITTER: Hosgood SA

PROVIDER: S-EPMC5887977 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Donation after circulatory death donors in lung transplantation.

Project description:Transplantation of any organ into a recipient requires a donor. Lung transplant has a long history of an inadequate number of suitable donors to meet demand, leading to deaths on the waiting list annually since national data was collected, and strict listing criteria. Before the Uniform Determination of Death Act (UDDA), passed in 1980, legally defined brain death in the U.S., all donors for lung transplant came from sudden death victims [uncontrolled Donation after Circulatory Death donors (uDCDs)] in the recipient's hospital emergency department. After passage of the UDDA, uDCDs were abandoned to Donation after Brain Death donors (DBDs)-perhaps prematurely. Compared to livers and kidneys, many DBDs have lungs that are unsuitable for transplant, due to aspiration pneumonia, neurogenic pulmonary edema, trauma, and the effects of brain death on lung function. Another group of donors has become available-patients with a devastating irrecoverable brain injury that do not meet criteria for brain death. If a decision is made by next-of-kin (NOK) to withdraw life support and allow death to occur by asphyxiation, with NOK consent, these individuals can have organs recovered if death occurs relatively quickly after cessation of mechanical ventilation and maintenance of their airway. These are known as controlled Donation after Circulatory Death donors (cDCDs). For a variety of reasons, in the U.S., lungs are recovered from cDCDs at a much lower rate than kidneys and livers. Ex-vivo lung perfusion (EVLP) in the last decade has had a modest impact on increasing the number of lungs for transplant from DBDs, but may have had a larger impact on lungs from cDCDs, and may be indispensable for safe transplantation of lungs from uDCDs. In the next decade, DCDs may have a substantial impact on the number of lung transplants performed in the U.S. and around the world.

| S-EPMC8662509 | biostudies-literature

Cytochrome P450 2E1 predicts liver functional recovery from donation after circulatory death using air-ventilated normothermic machine perfusion.

Project description:The optimal oxygen concentration is unclear for normothermic machine perfusion (NMP) of livers from donation after circulatory death (DCD). Our purposes were to investigate the effect of air-ventilated NMP on the DCD liver, analyze the underlying mechanism and select the targets to predict liver functional recovery with NMP. NMP was performed using the NMP system with either air ventilation or oxygen ventilation for 2 h in the rat liver following warm ischemia and cold-storage preservation. Proteomics and metabolomics were used to reveal the significant molecular networks. The bioinformation analysis was validated by administering peroxisome proliferator activator receptor-γ (PPARγ) antagonist and agonist via perfusion circuit in the air-ventilated NMP. Results showed that air-ventilated NMP conferred a better functional recovery and a less inflammatory response in the rat DCD liver; integrated proteomics and metabolomics analysis indicated that intrahepatic docosapentaenoic acid downregulation and upregulation of cytochrome P450 2E1 (CYP2E1) expression and activity were associated with DCD liver functional recovery with air-ventilated NMP; PPARγ antagonist worsened liver function under air-oxygenated NMP whereas PPARγ agonist played the opposite role. In conclusion, air-ventilated NMP confers a better liver function from DCD rats through the DAP-PPARγ-CYP2E1 axis; CYP2E1 activity provides a biomarker of liver functional recovery from DCD.

| S-EPMC9076671 | biostudies-literature

Cardiac function unchanged following reanimation with normothermic regional perfusion in donation after circulatory death.

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| S-EPMC9579788 | biostudies-literature

Kidney Transplants in Controlled Donation Following Circulatory Death, or Maastricht Type III Donors, With Abdominal Normothermic Regional Perfusion, Optimizing Functional Outcomes.

Project description:BackgroundWarm ischemia time and ischemia-reperfusion damage result in higher rates of delayed graft function and primary nonfunction in kidney transplants (KTs) from controlled donation after circulatory death (cDCD). This study aimed to assess early and late kidney function and patient and graft survival of KT from cDCD preserved with normothermic regional perfusion (NRP) and to compare with KT from brain death donors (DBDs) and cDCD preserved with rapid recovery (RR).MethodsPatients who received a KT at our institution from 2012 to 2018 were included, with a minimum follow-up period of 1 y. They were categorized by donor type and conditioning methods: DBD, cDCD with NRP, and cDCD with RR. Early and late graft function, along with patient and graft survival were analyzed in all groups.ResultsA total of 182 KT recipients were included in the study (98 DBD and 84 cDCD). Out of the cDCDs, 24 kidneys were recovered with the use of NRP and 62 with RR; 22 of the 24 kidneys were ultimately transplanted. The cDCD using NRP group showed lower rates of delayed graft function compared with the cDCD with RR group (36.3% versus 46.7%, P = 0.01). Also, primary nonfunction rates were lower in the cDCD using NRP group (4.5% versus 6.4% cDCD-RR and 10.2% DBD). Patient survival rates were >90% in all groups. No differences were found in graft survival rates at 1 y.ConclusionsThe use of abdominal NRP improves early function recovery of KT from cDCD, making their outcomes comparable with those of DBD.

| S-EPMC8288885 | biostudies-literature

Normothermic Ex Vivo Machine Perfusion for Liver Grafts Recovered from Donors after Circulatory Death: A Systematic Review and Meta-Analysis.

Project description:As a result of donation after circulatory death liver grafts' poor tolerance to cold storage, there has been increasing research interest in normothermic machine perfusion. This study aims to systematically review the current literature comparing normothermic perfusion to cold storage in donation after circulatory death liver grafts and complete a meta-analysis of published large animal and human studies. A total of nine porcine studies comparing cold storage to normothermic machine perfusion for donation after circulatory death grafts were included for analysis. There was a significant reduction in AST (mean difference -2291?U/L, CI (-3019, -1563); P ? 0.00001) and ALT (mean difference -175?U/L, CI (-266, -85); P = 0.0001), for normothermic perfusion relative to static cold storage, with moderate (I2 = 61%) and high (I2 = 96%) heterogeneity, respectively. Total bile production was also significantly higher (mean difference = 174?ml, CI (155, 193); P ? 0.00001). Further research focusing on standardization, performance of this technology following periods of cold storage, economic implications, and clinical trial data focused on donation after circulatory death grafts will be helpful to advance this technology toward routine clinical utilization for these grafts.

| S-EPMC5937385 | biostudies-literature

Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers.

Project description:Dual hypothermic oxygenated machine perfusion (DHOPE) of the liver has been advocated as a method to reduce ischemia/reperfusion injury (IRI). This study aimed to determine whether DHOPE reduces IRI of the bile ducts in donation after circulatory death (DCD) liver transplantation. In a recently performed phase 1 trial, 10 DCD livers were preserved with DHOPE after static cold storage (SCS; www.trialregister.nl NTR4493). Bile duct biopsies were obtained at the end of SCS (before DHOPE; baseline) and after graft reperfusion in the recipient. Histological severity of biliary injury was graded according to an established semiquantitative grading system. Twenty liver transplantations using DCD livers not preserved with DHOPE served as controls. Baseline characteristics and the degree of bile duct injury at baseline (end of SCS) were similar between both groups. In controls, the degree of stroma necrosis (P = 0.002) and injury of the deep peribiliary glands (PBG; P = 0.02) increased after reperfusion compared with baseline. In contrast, in DHOPE-preserved livers, the degree of bile duct injury did not increase after reperfusion. Moreover, there was less injury of deep PBG (P = 0.04) after reperfusion in the DHOPE group compared with controls. In conclusion, this study suggests that DHOPE reduces IRI of bile ducts after DCD liver transplantation. Liver Transplantation 24 655-664 2018 AASLD.

| S-EPMC5947530 | biostudies-literature

Lung Transplantation From Controlled and Uncontrolled Donation After Circulatory Death (DCD) Donors With Long Ischemic Times Managed by Simple Normothermic Ventilation and <i>Ex-Vivo</i> Lung Perfusion Assessment.

Project description:Donation after cardiac death (DCD) donors are still subject of studies. In this prospective cohort trial, we compared outcomes after lung transplantation (LT) of subjects receiving lungs from DCD donors with those of subjects receiving lungs from donation after brain death (DBD) donors (ClinicalTrial.gov: NCT02061462). Lungs from DCD donors were preserved in-vivo through normothermic ventilation, as per our protocol. We enrolled candidates for bilateral LT ≥14 years. Candidates for multi-organ or re-LT, donors aged ≥65 years, DCD category I or IV donors were excluded. We recorded clinical data on donors and recipients. Primary endpoint was 30-day mortality. Secondary endpoints were: duration of mechanical ventilation (MV), intensive care unit (ICU) length of stay, severe primary graft dysfunction (PGD3) and chronic lung allograft dysfunction (CLAD). 121 patients (110 DBD Group, 11 DCD Group) were enrolled. 30-day mortality and CLAD prevalence were nil in the DCD Group. DCD Group patients required longer MV (DCD Group: 2 days, DBD Group: 1 day, p = 0.011). ICU length of stay and PGD3 rate were higher in DCD Group but did not significantly differ. LT with DCD grafts procured with our protocols appears safe, despite prolonged ischemia times.

| S-EPMC9945516 | biostudies-literature

Heme oxygenase-1-modified bone marrow mesenchymal stem cells combined with normothermic machine perfusion to protect donation after circulatory death liver grafts.

Project description:BACKGROUND:Donation after circulatory death (DCD) liver grafts have a poor prognosis after transplantation. We investigated whether the outcome of DCD donor organs can be improved by heme oxygenase 1 (HO-1)-modified bone marrow-derived mesenchymal stem cells (BMMSCs) combined with normothermic machine perfusion (NMP), and explored its underlying mechanisms. METHODS:BMMSCs were isolated, cultured, and transduced with the HO-1 gene. An NMP system was established. DCD rat livers were obtained, preserved by different methods, and the recipients were divided into 5 groups: sham operation, static cold storage (SCS), NMP, BMMSCs combined with NMP, and HO-1/BMMSCs combined with NMP (HBP) groups. Rats were sacrificed at 1, 7, and 14?days after surgery; their blood and liver tissue samples were collected; and liver enzyme and cytokine levels, liver histology, high-mobility group box 1 (HMGB1) levels in monocytes and liver tissues, and expression of Toll-like receptor 4 (TLR4) pathway-related molecules were evaluated. RESULTS:After liver transplantation, the SCS group showed significantly increased transaminase levels, liver tissue damage, and shorter survival time. The HBP group showed lower transaminase levels, intact liver morphology, prolonged survival time, and decreased serum and liver proinflammatory cytokine levels. In the NMP and SCS groups, HMGB1 expression in the serum, monocytes, and liver tissues and TLR4 pathway-related molecule expression were significantly decreased. CONCLUSIONS:HO-1/BMMSCs combined with NMP exerted protective effects on DCD donor liver and significantly improved recipient prognosis. The effect of HO-1/BMMSCs was greater than that of BMMSCs and was mediated via HMGB1 expression and TLR4 pathway inhibition.

| S-EPMC7275432 | biostudies-literature

Hypothermic oxygenated machine perfusion promotes mitophagy flux against hypoxia ischemic injury in donation after circulatory death liver

Project description:HOPE is a dynamic preservation method to attenuate IRI in DCD liver. In a rat model of DCD liver, the protective mechanism of HOPE is probably by promoting mitophagy flux in response to hypoxia-ischemic injury. We performed gene expression profiling analysis using data obtained from RNA-seq of 4 different groups in DCD liver.

2022-10-15 | GSE215134 | GEO

Normothermic and hypothermic oxygenated perfusion for donation after circulatory death in kidney transplantation: do we pay higher risk of severe infection after transplantation?: a case report.

Project description:BACKGROUND:Normothermic and hypothermic oxygenated perfusion for donation after circulatory death in kidney transplantation are becoming popular in Italy, with the purpose of reducing the risk of primary non function and delayed graft function due to the prolonged warm ischemia time. Potential complications related to these procedures are currently under investigation and are continuously emerging with the increasing experience. Post-operative infections - in particular graft arteritis - are a rare complication but determine high risk of mortality and of graft loss. The acute onset of the arterial complications makes it very difficult to find an effective treatment, and early diagnosis is crucial for saving both patient and graft. Prevention of such infections in this particular setting are advisable. CASE PRESENTATION:We present a patient with an acute arterial rupture after transplantation of a DCD graft treated in-vivo hypothermic oxygenated perfusion. The cause was a severe arteritis of the renal artery caused by Candida krusei and Pseudomonas aeruginosa. We discussed our treatment and we compared it to the other reported series. CONCLUSION:Fungal infections in DCD transplant may be treacherous and strategies to prevent them should be advocated.

| S-EPMC7011237 | biostudies-literature

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