The impact of the SARS-CoV-2 pandemic and COVID-19 on lung transplantation in the UK: Lessons learned from the first wave.

BACKGROUND: Lung transplantation is particularly susceptible to the impact of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, and evaluation of changes to practice is required to inform future decision-making. METHODS: A retrospective review of the UK Transplant Registry (UKTR) and national survey of UK lung transplant centers has been performed. RESULTS: There was geographic variation in the prevalence of COVID-19 infection across the UK. The number of donors fell by 48% during the early pandemic period. Lung utilization fell to 10% (compared with 24% for the same period of 2019). The number of lung transplants performed fell by 77% from 53, March to May 2019, to 12. Seven (58%) of these were performed in a single-center, designated "COVID-light." The number of patients who died on the lung transplant waiting list increased, compared to the same period of 2019 (p = .0118). Twenty-six lung transplant recipients with confirmed COVID-19 infection were reported during the study period. CONCLUSION: As the pandemic continues, reviewing practice and implementing the lessons learned during this period, including the use of robust donor testing strategies and the provision of "COVID-light" hospitals, are vital in ensuring the safe continuation of our lung transplant program.

Heart transplantation in the UK during the first wave of the SARS-CoV-2 pandemic.

BACKGROUND: We aim to evaluate practice and understand the impact of the first wave of the SARS-CoV-2 pandemic on heart transplantation in the UK. METHODS: A retrospective review of the UK Transplant Registry (UKTR) and a national survey of UK heart transplant centers have been performed. The early pandemic period is defined here as 1 March to 31 May 2020. RESULTS: There was geographic variation in the prevalence of COVID-19 across the UK. All centers reported adaptations to maintain the safety of their staff, candidate, and recipient populations. The number of donors fell by 31% during the early pandemic period. Heart utilization increased to 35%, compared to 26% during the same period of 2019. The number of heart transplants was well maintained, across all centers, with 38 performed, compared to 41 during the same period of 2019, with no change in 30-day survival. Twenty-seven heart transplant recipients with confirmed COVID-19 infection were reported during the study period. CONCLUSION: All UK heart transplant centers have successfully adapted their programs to overcome the challenges of staff redeployment and ICU and hospital resource limitation, associated with the pandemic, whilst continuing heart transplant activity. On-going evaluation of practice changes, with sharing of lessons learned, is required as the pandemic continues.

Consensus statement on normothermic regional perfusion in donation after circulatory death: Report from the European Society for Organ Transplantation's Transplant Learning Journey.

Normothermic regional perfusion (NRP) in donation after circulatory death (DCD) is a safe alternative to in situ cooling and rapid procurement. An increasing number of countries and centres are performing NRP, a technically and logistically challenging procedure. This consensus document provides evidence-based recommendations on the use of NRP in uncontrolled and controlled DCDs. It also offers minimal ethical, logistical and technical requirements that form the foundation of a safe and effective NRP programme. The present article is based on evidence and opinions formulated by a panel of European experts of Workstream 04 of the Transplantation Learning Journey project, which is part of the European Society for Organ Transplantation.

A systematic review and meta-analyses of regional perfusion in donation after circulatory death solid organ transplantation.

In donation after circulatory death (DCD), (thoraco)abdominal regional perfusion (RP) restores circulation to a region of the body following death declaration. We systematically reviewed outcomes of solid organ transplantation after RP by searching PubMed, Embase, and Cochrane libraries. Eighty-eight articles reporting on outcomes of liver, kidney, pancreas, heart, and lung transplants or donor/organ utilization were identified. Meta-analyses were conducted when possible. Methodological quality was assessed using National Institutes of Health (NIH)-scoring tools. Case reports (13/88), case series (44/88), retrospective cohort studies (35/88), retrospective matched cohort studies (5/88), and case-control studies (2/88) were identified, with overall fair quality. As blood viscosity and rheology change below 20 °C, studies were grouped as hypothermic (HRP, ≤20 °C) or normothermic (NRP, >20 °C) regional perfusion. Data demonstrate that RP is a safe alternative to in situ cold preservation (ISP) in uncontrolled and controlled DCDs. The scarce HRP data are from before 2005. NRP appears to reduce post-transplant complications, especially biliary complications in controlled DCD livers, compared with ISP. Comparisons for kidney and pancreas with ISP are needed but there is no evidence that NRP is detrimental. Additional data on NRP in thoracic organs are needed. Whether RP increases donor or organ utilization needs further research.

The impact of severe acute kidney injury requiring renal replacement therapy on survival and renal function of heart transplant recipients - a UK cohort study.

Severe acute kidney injury (AKI), defined as requiring renal replacement therapy (RRT), is associated with higher mortality postheart transplantation, but its long-term renal consequences are not known. Anonymized data of 3365 patients, who underwent heart transplantation between 1995 and 2017, were retrieved from the UK Transplant Registry. Multivariable binary logistic regression was performed to identify risk factors for severe AKI requiring RRT, Kaplan-Meier analysis to compare survival and renal function deterioration of the RRT and non-RRT groups, and multivariable Cox regression model to identify predicting factors of mortality and end-stage renal disease (ESRD). 26.0% of heart recipients received RRT post-transplant. The RRT group has lower survival rates at all time points, especially in the immediate post-transplant period. However, conditional on 3 months survival, older age, diabetes and coronary heart disease, but not post-transplant RRT, were the risk factors for long-term survival. The predicting factors for ESRD were insulin-dependent diabetes, renal function at transplantation, eGFR decline in the first 3 months post-transplant, post-transplant severe AKI and transplantation era. Severe AKI requiring RRT post-transplant is associated with worse short-term survival, but has no impact on long-term mortality. It also accelerates recipients' renal function deterioration in the long term.

Effects of drug abuse, smoking and alcohol on donor hearts and lungs.

Potential heart and lung donors with a history of illicit drugs and/or smoking and alcohol are frequently offered, though there is no clear guidance on when it is safe to use these organs. A review of the literature on effects of drugs, alcohol and smoking on donor outcomes, and the effects of these on the intact heart and lung was undertaken. There has been a marked increase in deaths from opioid abuse in many developed countries, though recent evidence suggests that outcomes after cardiothoracic transplantation are equivalent to nonopioid donor causes of death. For donor smoking, there is an increased risk with lung transplantation; however, that risk is less when compared to further waiting on the transplant list for a nonsmoking alternative. Heavy alcohol consumption does not adversely affect heart transplantation, and there is no clear evidence of adverse outcomes after lung transplantation. There are no overall effects of cannabis or cocaine on survival after heart or lung transplantation. In all these cases, careful donor assessment can establish if a particular organ can be used. In most cases, use of drugs requires careful assessment, but is not in of itself a contraindication to cardiothoracic transplantation.

Paediatric donation after circulatory determined death heart transplantation using donor normothermic regional perfusion and ex situ heart perfusion: A case report.

This is a report of a unique DCD paediatric heart transplant whereby normothermic regional perfusion was used to assess DCD heart function after death followed by ex situ heart perfusion of the graft during transportation from donor to recipient hospitals. The DCD donor was a 9-year-old boy weighing 84 kg. The recipient was 7-year-old boy with failing Fontan circulation and weighed 23 kg. It was an ABO-compatible heart transplantation. The DCD heart was reperfused and assessed using normothermic regional perfusion followed by portable ex situ heart perfusion during transportation. The orthotopic heart transplantation was successful with good graft function and no evidence of rejection on endomyocardial biopsy at 30 days post-transplant. At 1-year follow-up, excellent graft function is maintained, and he is attending school with a good quality of life. DCD heart transplantation in children is a promising solution to reducing paediatric waiting times. The case demonstrates the feasibility of using normothermic regional perfusion in the donor and ex situ heart perfusion during graft transportation. This combination allowed a functional assessment whilst minimizing warm ischaemia resulting in a successful outcome. More research and long-term follow-up are needed in order to benefit from the huge potential that paediatric DCD heart transplantation has to offer.

Outcomes of lung transplantation in adults with bronchiectasis.

BACKGROUND: Lung transplantation is a well-established treatment for end-stage non-cystic fibrosis bronchiectasis (BR), though information regarding outcomes of transplantation remains limited. Our results of lung transplantation for Br are reported here. METHODS: A retrospective review of case notes and transplantation databases was conducted for patients that had underwent lung transplantation for bronchiectasis at the Freeman Hospital between 1990 and 2013. RESULTS: Fourty two BR patients underwent lung transplantation, the majority (39) having bilateral sequential lung transplantation. Mean age at transplantation was 47.1 years. Pre-transplantation osteoporosis was a significant non-pulmonary morbidity (48%). Polymicrobial infection was common, with Pseudomonas aeruginosa infection frequently but not universally observed (67%). Forced expiratory volume in 1 second (% predicted) improved from a pre-transplantation mean of 0.71 L (22% predicted) to 2.56 L (79 % predicted) at 1-year post-transplantation. Our survival results were 74% at 1 year, 64% at 3 years, 61% at 5 years and 48% at 10 years. Sepsis was a common cause of early post-transplantation deaths. CONCLUSIONS: Lung transplantation for end-stage BR is a useful therapeutic option, with good survival and lung function outcomes. Survival values were similar to other bilateral lung transplants at our centre. Pre-transplantation Pseudomonas infection is common.

Development of an ex vivo technique to achieve reanimation of hearts sourced from a porcine donation after circulatory death model.

BACKGROUND: This study reports on the development of a novel method for achieving ex vivo reanimation of hearts from a porcine donation after circulatory death (DCD) model without the use of donor pretreatment. METHODS: Porcine hearts (n = 23) were procured 10-29 min after confirmation of asystole. All hearts underwent initial flush with AQIX RS-I solution (London, UK). A 2-h preservation period followed: group 1 hearts (n1-n11) were preserved using static cold storage, group 2 hearts (n12-n17) were preserved using oxygenated, hypothermic machine perfusion (MP), and group 3 hearts (n18-n23) were subjected to retrograde oxygen persufflation. Reperfusion was performed on a Langendorff modification of a Model 33 Functional Circulation circuit. In hearts n16-n23, a dialysis circuit was incorporated into the circuit to facilitate removal of metabolites. The experimental protocol was allowed to follow an evolutionary course, with the aim of achieving greater success with reanimation. RESULTS: In group 1 (static cold storage), 7 of the 11 hearts (63.6%) achieved reanimation on the ex vivo circuit. Two of the six hearts (33.3%) in group 2 (MP) were successfully reanimated. All the six hearts (100%) in group 3 (persufflation) were successfully reanimated. The period of sustained reanimation increased when dialysis was incorporated into the circuit with a maximum of 300 min. CONCLUSIONS: Porcine DCD hearts after 29 min of warm ischemia can be reanimated using the method described. A mechanism of reoxygenation (oxygenated MP or coronary sinus oxygen persufflation) during preservation appears mandatory for hearts from DCDs. Persufflation was associated with a higher probability of successful reanimation. Dialysis in the warm phase was useful in removing metabolites that could interfere with reanimation. The results demonstrate the potential of DCDs to counter the decline affecting heart transplantation.

Aspiration and allograft injury secondary to gastroesophageal reflux occur in the immediate post-lung transplantation period (prospective clinical trial).

OBJECTIVES: To provide novel pilot data to quantify reflux, aspiration, and allograft injury immediately post-lung transplantation. BACKGROUND: Asymptomatic reflux/aspiration, associated with allograft dysfunction, occurs in lung transplant recipients. Early fundoplication has been advocated. Indications for surgery include elevated biomarkers of aspiration (bile salts) in bronchoalveolar lavage fluid (BALF). Measurements have been mostly documented after the immediate posttransplant period. We report the first prospective study of reflux/aspiration immediately posttransplantation to date. METHODS: Lung transplant recipients were recruited over 12 months. At 1 month posttransplantation, patients completed a Reflux Symptom Index questionnaire and underwent objective assessment for reflux (manometry and pH/impedance). Testing was performed on maintenance proton pump inhibitor. BALF was assessed for pepsin, bile salts, interleukin-8 and neutrophils. RESULTS: Eighteen lung transplant recipients, median age of 46 years (range: 22-59 years), were recruited. Eight of 18 patients had abnormal esophageal peristalsis. Five of 17 patients were positive on Reflux Symptom Index questionnaire. Twelve of 17 patients had reflux. Three patients exclusively had weakly acid reflux. Median acid exposure was 4.8% (range: 1%-79.9%) and median esophageal volume exposure was 1.6% (range: 0.7-5.5). There was a median of 72 reflux events (range: 27-147) per 24 hours. A correlation existed between Reflux Symptom Index score and proximal reflux (r = 0.533, P = 0.006). Pepsin was detected in 11 of 15 BALF samples signifying aspiration (median: 18 ng/mL; range: 0-43). Bile salts were undetectable, using spectrophotometry and rarely detectable using dual mass spectrometry (2/15) (levels 0.2 and 1.2 µmol/L). Lavage interleukin-8 and neutrophil levels were elevated. A correlation existed between proximal reflux events and neutrophilia (r = 0.52, P = 0.03). CONCLUSIONS: Lung transplant recipients should be routinely assessed for reflux/aspiration within the first month posttransplant. Reflux/aspiration can be present early postoperatively. Pepsin was detected suggesting aspiration. Bile salts were rarely detected. Proximal reflux events correlated with neutrophilia, linked to allograft dysfunction and mortality. These results support the need for early assessment of reflux/aspiration, which may inform fundoplication.

Effect of donor smoking on survival after lung transplantation: a cohort study of a prospective registry.

BACKGROUND: The risk that a positive smoking history in lung donors could adversely affect survival of transplant recipients causes concern. Conversely, reduction of the donor pool by exclusion of donors with positive smoking histories could compromise survival of patients waiting to receive a transplant. We examined the consequences of donor smoking on post-transplantation survival, and the potential effect of not transplanting lungs from such donors. METHODS: We analysed the effect of donor smoking on 3 year survival after first adult lung transplantation from brain-dead donors done between July 1, 1999, and Dec 31, 2010, by Cox regression modelling of data from the UK Transplant Registry. We estimated the effect of acceptance of lungs from donors with positive smoking histories on survival and compared it with the effect of remaining on the waiting list for a potential transplant from a donor with a negative smoking history donor, by analysing all waiting-list registrations during the same period with a risk-adjusted sequentially stratified Cox regression model. FINDINGS: Of 1295 lung transplantations, 510 (39%) used lungs from donors with positive smoking histories. Recipients of such lungs had worse 3 year survival after transplantation than did those who received lungs from donors with negative smoking histories (unadjusted hazard ratio [HR] 1·46, 95% CI 1·20-1·78; adjusted HR 1·36, 1·11-1·67). Independent factors affecting survival were recipient's age, donor-recipient cytomegalovirus matching, donor-recipient height difference, donor's sex, and total ischaemic time. Of 2181 patients registered on the waiting list, 802 (37%) died or were removed from the list without receiving a transplant. Patients receiving lungs from donors with positive smoking histories had a lower unadjusted hazard of death after registration than did those who remained on the waiting list (0·79, 95% CI 0·70-0·91). Patients with septic or fibrotic lung disease registered in 1999-2003 had risk-adjusted hazards of 0·60 (95% CI 0·42-0·87) and 0·39 (0·28-0·55), respectively. INTERPRETATION: In the UK, an organ selection policy that uses lungs from donors with positive smoking histories improves overall survival of patients registered for lung transplantation, and should be continued. Although lungs from such donors are associated with worse outcomes, the individual probability of survival is greater if they are accepted than if they are declined and the patient chooses to wait for a potential transplant from a donor with a negative smoking history. This situation should be fully explained to and discussed with patients who are accepted for lung transplantation. FUNDING: National Health Service Blood and Transplant.

Organ Transplants From Deceased Donors With Primary Brain Tumors and Risk of Cancer Transmission.

Importance: Cancer transmission is a known risk for recipients of organ transplants. Many people wait a long time for a suitable transplant; some never receive one. Although patients with brain tumors may donate their organs, opinions vary on the risks involved. Objective: To determine the risk of cancer transmission associated with organ transplants from deceased donors with primary brain tumors. Key secondary objectives were to investigate the association that donor brain tumors have with organ usage and posttransplant survival. Design, Setting, and Participants: This was a cohort study in England and Scotland, conducted from January 1, 2000, to December 31, 2016, with follow-up to December 31, 2020. This study used linked data on deceased donors and solid organ transplant recipients with valid national patient identifier numbers from the UK Transplant Registry, the National Cancer Registration and Analysis Service (England), and the Scottish Cancer Registry. For secondary analyses, comparators were matched on factors that may influence the likelihood of organ usage or transplant failure. Statistical analysis of study data took place from October 1, 2021, to May 31, 2022. Exposures: A history of primary brain tumor in the organ donor, identified from all 3 data sources using disease codes. Main Outcomes and Measures: Transmission of brain tumor from the organ donor into the transplant recipient. Secondary outcomes were organ utilization (ie, transplant of an offered organ) and survival of kidney, liver, heart, and lung transplants and their recipients. Key covariates in donors with brain tumors were tumor grade and treatment history. Results: This study included a total of 282 donors (median [IQR] age, 42 [33-54] years; 154 females [55%]) with primary brain tumors and 887 transplants from them, 778 (88%) of which were analyzed for the primary outcome. There were 262 transplants from donors with high-grade tumors and 494 from donors with prior neurosurgical intervention or radiotherapy. Median (IQR) recipient age was 48 (35-58) years, and 476 (61%) were male. Among 83 posttransplant malignancies (excluding NMSC) that occurred over a median (IQR) of 6 (3-9) years in 79 recipients of transplants from donors with brain tumors, none were of a histological type matching the donor brain tumor. Transplant survival was equivalent to that of matched controls. Kidney, liver, and lung utilization were lower in donors with high-grade brain tumors compared with matched controls. Conclusions and Relevance: Results of this cohort study suggest that the risk of cancer transmission in transplants from deceased donors with primary brain tumors was lower than previously thought, even in the context of donors that are considered as higher risk. Long-term transplant outcomes are favorable. These results suggest that it may be possible to safely expand organ usage from this donor group.

A human model of bilateral pulmonary vein sampling to assess the effects of one-lung ventilation on neutrophil function.

BACKGROUND: Neutrophil activation drives lung complications after cardiopulmonary bypass (CPB). Evidence suggests the healthy, ventilated lung may beneficially re-condition pro-inflammatory neutrophils. However, evidence in humans is lacking, due to a paucity of good models. CPB with simultaneous central venous and bilateral pulmonary vein sampling provides an opportunity to model effects of one-lung ventilation. The study's primary objectives were to establish a model of intra-operative, bilateral pulmonary vein sampling and to determine whether neutrophil function differed after passing through inflated or deflated lungs. METHODS: Seventeen patients having "on pump" coronary artery bypass grafting (CABG) with one-lung ventilation (in two cohorts with tidal volume 2ml kg-1 and FiO2 0.21, or tidal volume 4 ml kg-1 and FiO2 0.5 respectively) were recruited. Cohort 1 consisted of 9 patients (7 male, median age 62.0 years) and Cohort 2 consisted of 8 male patients (median age 65.5 years). Recruitment was via prospective screening of scheduled elective and non-elective CABG procedures with cardiopulmonary bypass. Each patient had five blood samples taken-central venous blood pre-operatively; central venous blood pre-CPB; central venous blood post-CPB; pulmonary venous blood draining the ventilated lung post-CPB; and pulmonary venous blood draining the deflated lung post-CPB. Neutrophil phagocytosis and priming status were quantified. Plasma cytokines were measured. RESULTS: Phagocytosis and priming were not significantly different in neutrophils returning from the ventilated lung as compared to the non-ventilated lung. Plasma IL-6, IL-8 and IL-10 were significantly elevated by CPB. CONCLUSIONS: The intra-operative, bilateral pulmonary vein sampling model provides unique opportunities to assess biological effects of interventions to one lung, with the other lung acting as an internal control. Single-lung ventilation during CPB had no significant effects on neutrophil function.

Ex situ heart perfusion: The past, the present, and the future.

Despite the advancements in medical treatment, mechanical support, and stem cell therapy, heart transplantation remains the most effective treatment for selected patients with advanced heart failure. However, with an increase in heart failure prevalence worldwide, the gap between donor hearts and patients on the transplant waiting list keeps widening. Ex situ machine perfusion has played a key role in augmenting heart transplant activities in recent years by enabling the usage of donation after circulatory death hearts, allowing longer interval between procurement and implantation, and permitting the safe use of some extended-criteria donation after brainstem death hearts. This exciting field is at a hinge point, with 1 commercially available heart perfusion machine, which has been used in hundreds of heart transplantations, and a number of devices being tested in the pre-clinical and Phase 1 clinical trial stage. However, no consensus has been reached over the optimal preservation temperature, perfusate composition, and perfusion parameters. In addition, there is a lack of objective measurement for allograft quality and viability. This review aims to comprehensively summarize the lessons about ex situ heart perfusion as a platform to preserve, assess, and repair donor hearts, which we have learned from the pre-clinical studies and clinical applications, and explore its exciting potential of revolutionizing heart transplantation.

Primary bronchial epithelial cell culture from explanted cystic fibrosis lungs.

Lung disease is responsible for more than 95% of morbidity and mortality in cystic fibrosis. The exact pathogenesis of cystic fibrosis lung disease remains poorly understood. Experimental models are therefore vital for use in research. Animal models and immortalized cell lines both have inherent limitations. Explanted lungs removed from people with cystic fibrosis at the time of transplantation represent a potentially valuable but technically and logistically challenging source of primary cystic fibrosis bronchial epithelial cells. In this study, pieces of segmental bronchus from explanted lungs were treated with patient-specific antimicrobials prior to isolation of bronchial epithelial cells. Cultured cells were characterized by their morphology under light microscopy, cytokeratin and hematoxylin-eosin staining, and electrophysiological profile. Primary bronchial epithelial cells were successfully cultured from 15 of 22 patients attempted. The cells exhibited typical epithelial morphology, staining for cytokeratin, lack of responsiveness to forskolin treatment, and remained viable after storage in liquid nitrogen. Seven unsuccessful cultures failed due to early infection with bacteria known to colonize the airways pretransplant. The results show that primary bronchial epithelial cell culture is possible from explanted cystic fibrosis lungs. This provides an important cellular model to elucidate the pathogenic mechanisms in cystic fibrosis lung disease and to investigate potential therapeutic targets.

Flavin Mononucleotide as a Biomarker of Organ Quality-A Pilot Study.

BACKGROUND: Flavin mononucleotide (FMN), released from damaged mitochondrial complex I during hypothermic liver perfusion, has been shown to be predictive of 90-day graft loss. Normothermic machine perfusion (NMP) and normothermic regional perfusion (NRP) are used for organ reconditioning and quality assessment before transplantation. This pilot study aimed to investigate the changes of FMN levels during normothermic reperfusion of kidneys, livers, and lungs and examine whether FMN could serve as a biomarker to predict posttransplant allograft quality. METHODS: FMN concentrations, in perfusates collected during NMP of kidneys, abdominal NRP, and ex vivo lung perfusion, were measured using fluorescence spectrometry and correlated to the available perfusion parameters and clinical outcomes. RESULTS: Among 7 transplanted kidneys out of the 11 kidneys that underwent NMP, FMN levels at 60 minutes of NMP were significantly higher in the allografts that developed delayed graft function and primary nonfunction (P = 0.02). Fifteen livers from 23 circulatory death donors that underwent NRP were deemed suitable for transplantation. Their FMN levels at 30 minutes of NRP were significantly lower than those not procured for transplantation (P = 0.004). In contrast, little FMN was released during the 8 lung perfusions. CONCLUSIONS: This proof of concept study suggested that FMN in the perfusates of kidney NMP has the potential to predict posttransplant renal function, whereas FMN at 30 minutes of NRP predicts whether a liver would be accepted for transplantation. More work is required to validate the role of FMN as a putative biomarker to facilitate safe and reliable decision-making before embarking on transplantation.

Novel Organ Perfusion and Preservation Strategies in Transplantation - Where Are We Going in the United Kingdom?

This review article focuses on current clinical outcomes with novel perfusion strategies in organ transplantation. Broadly, these approaches can be divided into in situ regional perfusion in the donor and ex situ machine perfusion of individual organs. In both settings, hypothermic and normothermic techniques are in clinical use. Evidence from full text articles, abstracts, and data presented at scientific meetings has been considered. Animal studies have been excluded. The review focuses on kidney, liver, pancreas, heart, and lungs. The level of evidence ranges from quasi-experimental work in human pancreas to multiple meta-analyses of Randomized Controlled Trials for hypothermic machine perfusion of kidneys. The data in this review were presented to experts in organ perfusion and preservation at the National Health Service Blood and Transplant Preservation and Perfusion Future Strategy Summit in London in October 2018. The outcomes of the meeting are discussed in the review after due consideration of the available evidence base.

Norepinephrine and arginine vasopressin increase hepatic but not renal inflammatory activation during hemodynamic resuscitation in a rodent model of brain-dead donors.

OBJECTIVES: Hypotension that occurs after brain death causes a deterioration in organ function, which in turn restricts the number of organs that can be retrieved and leads to graft dysfunction. The correction of hypotension by the administration of norepinephrine increases the number of organs suitable for retrieval but is associated with cardiac allograft failure. Arginine vasopressin is relatively less cardiotoxic; however, the effect of that drug on intra-abdominal organs is unknown. We used a rodent model and real-time reverse transcription polymerase chain reaction to assess changes in the expression of inflammatory mediators in livers and kidneys that occurred in response to resuscitation with those drugs. MATERIALS AND METHODS: Fifty outbred male Wistar rats were anesthetized, and an intracranial balloon was inserted. In 35 rats, the balloon was inflated to induce brain death and subsequent hypotension. In 20 of those rats, hypotension was corrected with either norepinephrine (n = 10) or vasopressin (n = 10), while the remaining 15 rats received no resuscitation. Brain death was not induced in 15 rats that did not become hypotensive or receive resuscitation. Organs were retrieved 30 minutes, 2 hours, and 5 hours after balloon insertion, and inflammatory activation was assessed via real-time reverse transcription polymerase chain reaction. RESULTS: Significant time-dependent up-regulation of CXC motif chemokine ligand 1, interleukin-1beta, and heme oxygenase 1 occurred after brain death. Significantly greater up-regulation of CXC motif chemokine ligand and interleukin-1beta occurred in the livers of rats that received norepinephrine and vasopressin than in those that received no resuscitation. No increase in the expression of those mediators was noted in the kidneys. CONCLUSIONS: This study showed that both norepinephrine and vasopressin amplified the inflammatory response that followed brain death in the livers, but not the kidneys, of rats in this model.

Mitochondrial Haplogroup and the Risk of Acute Kidney Injury Following Cardiac Bypass Surgery.

Although mitochondrial dysfunction plays a key role in the pathophysiology of acute kidney injury (AKI), the influence of mitochondrial genetic variability in this process remains unclear. We explored the association between the risk of post-cardiac bypass AKI and mitochondrial haplotype - inherited mitochondrial genomic variations of potentially functional significance. Our single-centre study recruited consecutive patients prior to surgery. Exclusions included stage 5 CKD, non-Caucasian race and subsequent off-pump surgery. Haplogroup analysis allowed characterisation of the study population using the common mutations and by phylogenetic supergroup (WXI and HV). Chi-square tests for association allowed the identification of potential predictors of AKI for use in logistic regression analysis. AKI occurred in 12.8% of the study population (n = 881; male 69.6%, non-diabetic 78.5%, median (interquartile range) age 68.0 (61.0-75.0) years). The haplogroup profile comprised H (42.7%), J (12.1%), T (10.9%), U (14.4%) and K (7.6%). Although the regression model was statistically significant (χ2 = 95.483, p < 0.0005), neither the phylogenetic supergroups nor any individual haplogroup was a significant contributor. We found no significant association between common European haplogroups and the risk of post-cardiac bypass AKI. However, given the major role of mitochondrial dysfunction in AKI, there is a need to replicate our findings in other cohorts and with other aetiologies of AKI.

Lung transplantation from the non-heart beating donor.

The inflated lung, with its unique tolerance of the absence of a circulation, is particularly suited to retrieval from the non-heart beating donor. Absence of some of the squeal of brain death may be a further potential advantage. This concept has been embraced by several centers around the world, with promising early results.