Modifying Donor Organ Retrieval and Preservation to Enhance Transplant Outcomes

The last 1-2 decades have seen remarkable advances in organ procurement and preservation practices, especially with renewed enthusiasm for machine perfusion (MP) technology. However, cold static storage (CS) remains the most popular world-wide approach for the preservation of organs such as the kidneys, liver, and pancreas, largely due to its simplicity. It is clear that CS techniques have limited potential for further improvement, and will likely be supplanted and/or supplemented with MP technologies over the coming years due to the reparative, resuscitative, and assessment capabilities afforded by MP. This is especially important as we increase our utilisation of marginal and/or donation after circulatory death (DCD) organs to meet the ever-increasing demand requirements for transplantation. This dissertation explores selected aspects of abdominal organ procurement and preservation as targets for improvement and/or modification with the aim to enhance recipient transplantation outcomes. The kidney is used as a model organ for the development and exploration of MP as a means to ameliorate transplant organ ischaemia-reperfusion injury (IRI), including through the targeted delivery of anti-IRI drugs. In contrast, the optimization of CS protocols, including identification of ideal perfusion fluids and in situ perfusion routes, forms the basis for liver and pancreas transplantation work in this thesis. Such investigations are necessary to promote uniformity of practice between centres, and allow appropriate comparisons between MP and CS. The kidney MP work was guided by a systematic review and meta-analysis comparing MP and CS in the clinical and pre-clinical setting. Although hypothermic MP (HMP) was shown to enhance short-term graft outcomes, results were equivocal with respect to graft survival, especially in the DCD setting. Preliminary evidence indicated the potential superiority of normothermic MP (NMP) above HMP or CS, which may be further enhanced by using NMP as a conduit for directed drug delivery to the kidney to ameliorate IRI. We therefore developed and optimized a local NMP set-up using a series of porcine kidneys, which was then utilized to deliver the anti-IRI agent CD47-blocking antibody (αCD47Ab) in a porcine DCD model. The significant potential of this agent was initially confirmed by testing in a murine model of severe warm IRI, including its comparative efficacy to two other promising IRI agents, soluble complement receptor 1 (sCR1), and recombinant thrombomodulin, and also sCR1 in combination with αCD47Ab. αCD47Ab was successfully delivered to porcine DCD kidneys using NMP, with subsequent downstream positive impacts upon renal perfusion, and some functional and IRI-related parameters. The clinical utilisation of renal NMP has so far been limited to the UK, and this modality has not been tested in human kidneys in Australasia. Furthermore, the mechanistic basis of brief renal NMP is not entirely clear. Therefore, and as a prelude to a phase I clinical trial, NMP was tested in discarded deceased donor human kidneys. Fifteen kidneys were obtained from 10 donors, and successfully underwent NMP. NMP was especially effective for assessing and improving DCD kidneys discarded for poor macroscopic perfusion at retrieval. Flow cytometry analyses showed evidence of a massive passenger leukocyte efflux during NMP. In paired kidney analyses, one hour of NMP was shown to be superior to CS alone after simulated transplantation using ex vivo whole allogeneic blood reperfusion, in terms of renal perfusion and functional parameters. Whole transcriptome RNA sequencing revealed NMP-mediated induction of protective stress and inflammatory-related pathways, in addition to a reduction in cell death pathways. Accordingly, immunofluorescence techniques confirmed a reduction in cell death and IRI in NMP kidneys compared to their CS counterparts. CS and procurement techniques formed the basis of liver and pancreas transplantation-related studies conducted for this thesis. Firstly, we showed that blood transfusion requirements can be significantly reduced in recipients if the pancreas is retrieved using ultrasonic shears (Harmonic Scalpel), implying a reduction in procedural risk and recipient sensitization. Two systematic reviews and meta-analyses were then conducted to ascertain optimal in situ perfusion/preservation fluids, and perfusion routes, during procurement of pancreatic and hepatic allografts. There was a lack of overwhelming evidence favouring any specific preservation fluid, although University of Wisconsin solution will likely remain the solution of choice, especially for the pancreas. Furthermore, in standard criteria donors, aortic-only perfusion was found to produce equivalent liver transplant outcomes in comparison to dual (aorto-portal perfusion). However, existing studies included small patient numbers and short periods of follow-up. We therefore compared aortic and dual perfusion during liver retrieval using the Australia and New Zealand Liver Transplant Registry, which provided a much larger patient cohort with prolonged follow-up. This study confirmed the equivalence of aortic-only and dual perfusion in standard criteria liver donors, however there was also evidence indicating the superiority of dual perfusion in a subset of suboptimal/higher risk donors. Overall, this thesis expounds upon the putative benefits of NMP in kidney transplantation, including by directed drug delivery targeting the IRI cascade, and also enhances our understanding of optimal perfusion routes and preservation fluids for the liver and pancreas. The ultimate aim is to facilitate expansion of the donor pool whilst simultaneously enhancing recipient transplantation outcomes through the evidence-based implementation of technologies and techniques in a unified and coordinated manner

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research