Approved Research Projects

These projects have been approved by the QUOD Steering Committee.

Do you have a status update for us? Please email quod-research@nds.ox.ac.uk to let us know.

RAP001: Proteomic signatures in donor blood as diagnostic tools of donor kidney quality and predictors of 12-month outcomes in kidney transplantation
Maria Kaisar
Despite the persistent shortage of donor organs, many organs obtained from older, higher-risk donors are deemed unsuitable for transplantation and discarded. With a growing ageing population it is vital to develop tools that will allow clinicians to accurately assess donor organ quality prior to organ explantation and make informed decisions on which organs should be discarded or transplanted. To address this clinical challenge, we propose a discovery study aiming to identify proteomic signatures in the donor that are predictive of 12-month kidney function in the recipient, following transplantation. Our proposed research will lead to the development of clinical tools for donor organ quality assessment that will minimise donor organ discard and, as a result, increase the number of grafts available for transplantation. Using label-free proteomic analysis we will study the alterations in protein expression among donor groups and we will further improve our understanding of the underlying mechanisms of kidney ischaemia or repair.
Approved by Steering Committee:2 June 2015
Feedback received:Results expected March 2020
RAP002: Molecular signatures of donor kidney quality as predictors of long term outcomes
Maria Kaisar
Despite the persistent shortage of donor organs, many organs obtained from older, higher-risk donors are deemed unsuitable for transplantation and discarded. With a growing ageing population it is vital to develop tools that will allow clinicians to accurately assess donor organ quality prior to organ explantation and make informed decisions on which organs should be discarded or transplanted. We have embarked on the discovery of proteomic signatures in donor blood and urine that are related to donor kidney quality and are predictive of kidney function 12 months following transplantation. In order to correlate the differentially regulated proteins in blood and urine with the pathophysiological changes in kidney, we propose to analyse donor biopsies by mass spectrometry technologies, biochemical techniques, histology and immunohistochemistry. This unique approach will support our work of developing diagnostic tools for donor organ quality in parallel with expanding our understanding of the underlined mechanisms of kidney ischaemia and identifying new targets of intervention.
Approved by Steering Committee:21 August 2015
Feedback received:Results expected December 2020
RAP003/004: Investigation of injury pathways and mitochondrial bioenergetics in kidneys and livers after brain (DBD) and circulatory death (DCD)
Letizia Lo Faro
The shortage of organs for transplantation has led to the expansion of the selection criteria to include many organs that would have once been considered unsuitable. These include organs from older donors presenting co-morbidities or donors deceased following a cerebrovascular event. Although organs from living donors have superior long-term survival, donation after brain death (DBD) and donation after circulatory death (DCD) are well established procedures. The organs retrieved from deceased donors have generally gone through various physiological changes and, to different extents, have been subjected to warm ischaemia. Taken together, these factors contribute to making the organs more susceptible to injury upon transplantation, if compared to living donor organs and influence the organ survival/function post-transplantation. By investigating which molecular processes are dysregulated in poorly performing transplanted organs at time of donation, it will be possible to identify novel potential therapeutic targets to improve quality in organ donation.
Approved by Steering Committee:21 August 2015
Feedback received:NO
RAP005/006: Assessment of the feasibility and potential impact of a kidney and liver donor histopathology service in the UK
Simon Knight
Transplantation is the preferred treatment for patients with kidney and liver failure. One of the main problems faced by transplant teams is the gap between the number of suitable organ donors and the number of patients on the transplant waiting list. To reduce this gap, we are using increasing numbers of organs from older, less healthy donors. As this becomes more common, it is important that we find reliable ways to predict which of these organs will work well after transplant to help us decide which ones to accept. Therefore, having a pathology service that could help predict outcomes from a pre-transplantation biopsy could be invaluable.
Approved by Steering Committee:27 April 2016
Feedback received:Awaiting funding
RAP 009: Method optimisation as a prelude study of Proteomic and MicroRNA analysis of Laser Capture Micro (LCM) dissected proximal tubules obtained from DBD kidney biopsies (delayed graft function (DGF) vs immediate function (IF))
Maria Kaisar
We hypothesise that by isolating proximal tubule structures from DBD and DCD kidneys and analysing these structures by a combination of proteomics and microRNA techniques, we will identify markers that are differentially expressed among DGF vs IF outcomes post-transplantation. These markers can play an important role in assessing kidney quality prior to kidney retrieval. The combination of these novel techniques of LCM and proteomics requires a number of optimisation steps prior to testing our hypothesis. In order to identify how many slides we need to extract enough protein for this analysis we have to test the proposed optimisation protocol.
Approved by Steering Committee:29 May 2015
Feedback received:On hold
RAP010: Investigation of the mechanisms of injury and stress response in kidneys from DBD donors—Correlation with delayed graft function (DGF) vs immediate function (IF)
Maria Kaisar
Transplantation represents a very successful treatment for end stage organ failure and several other pathologies. Unfortunately, it is increasingly evident that a great disparity between organ supply and demand exists. Despite this, paradoxically, many organs are currently discarded, due to the uncertainties in objectively assessing their viability. Therefore it is necessary to find better and more objective ways of assessing organ viability and suitability for transplantation.
In a previous study, we identified a proteomic signature of serum samples from DBD donors, which correlated significantly with kidney DGF in the recipient. Many proteins associated with inflammatory and cell-death pathways were found to be significantly up-regulated in the DGF group compared to the IF group, while others were solely expressed in the DGF group, providing a characteristic profile. The aim of the present work is to validate the findings and signatures from our previous study in kidney tissue biopsies from DBD donors, grouped according to clinical outcome post transplantation (DGF vs IF). Once validated, these profiles can provide a useful tool for the correct assessment of organ quality.
Approved by Steering Committee:7 July 2015
Feedback received:Transplantation 2019;103: 323–328
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RAP012: Urinary MicroRNAs as predictors of graft ischaemic injury
Donald Fraser
We have recently shown that urinary microRNAs can be used to measure Delayed Graft Function in kidney transplant patients. To confirm these findings, we need to validate in an independent larger cohort of patients. Delayed Graft Function (DGF) is a common and serious problem following kidney transplantation, as a consequence of Ischaemia-Reperfusion Injury (IRI). Identifying a biomarker of the extent of IRI, and hence risk of DGF, will allow us to predict and appropriately tailor post-op management for transplant patients. It would also help us to test treatments that might help the transplanted kidney recover function more quickly.
Approved by Steering Committee:21 August 2015
Feedback received:YES
RAP013: Circulating unmethylated DNA and beta-cell death as a biomarker of graft dysfunction in pancreas transplantation
Iestyn Shapey
There is a shortage of high quality organ donors appropriate for pancreas transplantation—in 2015, only 35% of pancreases that were offered for transplantation were eventually transplanted. This is coupled with the absence of a robust tool for objective assessment of their suitability for transplantation. The aim of this project is to identify a test with the potential to accurately inform surgeons whether the pancreas cells are alive and working, and hence its suitability for transplantation. The test could also be used to monitor transplant recipients afterwards for signs of worsening performance and loss of the transplanted pancreas.
Approved by Steering Committee:6 November 2015
Feedback received:NO
RAP014: Improving graft function in transplantation with Normothermic Regional Perfusion: A pilot study to investigate the underlying mechanism
Andrew Sutherland
Organs recovered from donors after circulatory death suffer a period of warm ischaemia (damage due to lack of oxygen) before cold storage, leading to impaired organ function. A period of normothermic regional perfusion in the donor (similar to a heart–lung bypass machine), may reverse these effects and improve graft function as well as leading to an increase in the number of livers and kidneys available for transplantation. We still do not fully understand the mechanism by which normothermic perfusion works. This pilot study will investigate the effect of NRP on gene expression and microRNA signatures to better understand the therapeutic effect of NRP and how this differs from the standard methods of organ recovery. We will also aim to identify markers that can be used for the evaluation of organs prior to transplantation.
Approved by Steering Committee:28 October 2015
Feedback received:NO
RAP015: Pre-donation biomarkers to assess quality of kidney graft of DBD and DCD kidney grafts.
Christopher Chalklin
A retrospective study of pre-donation biomarkers from the serum of brain-death and cardiac-death kidney donors. We will assess whether there is any correlation between NGAL and KIM-1 levels in serum of donors compared to outcomes of kidney transplant immediately post-operatively and at one year. We hypothesise that these serum biomarkers could be used to predict post-operative outcomes.
Approved by Steering Committee:20 November 2015
Feedback received:NO
RAP016: Proteomics of urinary and blood exosomes to identify biomarkers associated with transplantation outcomes
Honglei Huang
Despite a shortage of organs for transplantation, many high-risk organs are still discarded due to lack of an objective organ-quality assessment. We propose an organ-quality assessment by studying the exosomes extracted from urine and blood samples from LD, DBD and DCD donors. A panel of exosome proteins will be used to examine organ quality and distinguish LD from DBD and DCD. We will also investigate whether those exosome proteins can be used to associate with one-year transplantation outcome.
Approved by Steering Committee:19 July 2016
Feedback received:NO
RAP017: Investigation of markers of injury and mitochondrial bioenergetics in kidneys from donors with acute kidney injury (AKI)
Catherine Boffa
Transplantation is the preferred treatment for patients with kidney failure. One of the main problems faced by transplant teams is the gap between number of suitable organ donors and the number of patients on the transplant waiting list. To reduce this gap, we are using increasing numbers of organs from older, less healthy donors, and this may include donors who have some evidence of acute kidney injury (AKI). Although we know that acute kidney injury may be reversible, it is important that we find reliable ways to predict which of these organs will work well after transplant to help us decide which ones to accept.
Approved by Steering Committee:17 May 2016
Feedback received:NO
RAP018: Distinguishing between different types of cytomegalovirus infection and their effect on the recipient including long-term kidney function.
Paul Griffiths
Transplantation can transmit cytomegalovirus from donor to recipient. The need for immunosuppressive drugs can also make latent virus reappear in the recipient. Transplant centres routinely use antiviral drugs to reduce the chance of this virus causing serious disease. We wish to use new laboratory techniques to define the strains of CMV found after transplant so that reactivation (recipient source of virus) can be distinguished from primary infection and reinfection (donor source of virus). Knowing how frequently these types of infection occur will help us design vaccine trials to give immunity against CMV to recipients before they are transplanted.
Approved by Steering Committee:6 April 2016
Feedback expected:March 2022 (initial feedback received November 2020)
RAP019/20: Investigation of transcriptional signatures predictive of suboptimal short- and long-term outcomes in deceased circulatory death kidney transplants
Menna Clatworthy
Transplantation is the optimal treatment for end-stage kidney failure; however there is a limited supply of suitable organs and a need for better markers to inform the decision to transplant a kidney, whilst minimising patient risk and organ wastage. Currently, we use a scoring system based on how the kidney looks under a microscope but we know that, although this improves organ use, it still isn’t perfect. We want to identify markers that better predict how good a transplant will be. To do this, we will measure the expression of genetic information in kidney biopsies using a method that can read-out hundreds of thousands of genes. We can then select a small number of markers from this big group that best associate with bad or good outcomes. We hope this will provide a way of optimising the use of organs for transplantation thereby maximising patient benefit.
Approved by Steering Committee:20 July 2016
Feedback received:NO
RAP021: Beta cell death as an assessment tool for selecting donors for pancreas transplantation
Iestyn Shapey
Pancreas transplantation can be life-saving for people with the most complex type 1 diabetes. Due to the shortage of organs for transplantation we urgently need to improve methods for selecting good quality organs. Organ donors experience considerable stress to their bodies in the period prior to donation which can adversely affect the donated organs. It is unknown whether these effects are reversible (cell-stress) or not (cell-death). This project aims to determine whether a blood test to determine cell death has the potential to accurately inform surgeons whether the pancreas cells are alive and working and hence help objectively determine the suitability for transplantation.
Approved by Steering Committee:14 November 2016
Feedback received:NO
RAP024: Systematic study of serum markers of brain injury in DBD organ donors
Katarzyna Bera
Kidney transplantation provides the ideal treatment for end-stage renal failure. Cadaveric organs from deceased donors after brain death are an important source of organs for transplantation. However, it is not entirely understood how brain death can affect the donated organ in the short and long term. This study aims to provide a first systematic study of serum proteins in the deceased donor and try to identify protein markers important for long term outcome. We will use a proteomics approach to characterise and quantify the changes in protein networks during the donor management period before organ procurement.
Approved by Steering Committee:6 April 2017
Feedback received:NO
RAP025: Developing diagnostics of donor organ quality predictive of transplantation outcomes
Maria Kaisar
Despite the persistent shortage of donor organs, many organs obtained from older higher-risk donors are deemed unsuitable for transplantation and discarded. With a growing ageing population it is vital to develop novel diagnostic assays that will allow accurate assessment of donor organ quality. Diagnostics of donor organ quality will support informed decisions of organ utilisation and organ allocation on the basis of long-term post-transplant allograft function. Our previous work on discovery of proteomic/peptidomic signatures in donor kidney tissue, blood and urine has shown that it is feasible to discriminate amongst donor kidneys on the basis of suboptimal or good post-transplantation outcomes. This proposal aims to 1) further validate these findings and evaluate the association to long term outcomes and 2) compare the utility of a diagnostic proteomic profile to Remuzzi scoring and assess whether a panel of proteomic markers adds value in the evaluation of donor kidneys.
Approved by Steering Committee:14 December 2017
Feedback expected:December 2020
RAP026: Unravelling the biological mechanisms contributing to delayed graft function and to different lengths of recovery after deceased donor kidney transplantation
Kaithlyn Rozenberg
Transplantation is the gold-standard treatment for end-stage renal disease. Due to the high demand of organs for transplantation, more high-risk donors are currently used. One of the primary early complications after transplantation is delayed graft function (DGF). DGF is a manifestation of acute kidney injury (AKI), which is recoverable and mostly defined as need for dialysis in the first week post-transplant. Previous studies have shown that DCD donors have higher risk of DGF. Interestingly, DGF has been found to be associated with reduced graft survival in DBD transplants, but does not seem to impact DCD grafts. Correlation between duration of DGF and outcome is not known, with DGF ranging from 1 to 48 days, with reported average durations of 10 to 16 days. By studying the alterations of cellular pathways in different types of donor kidney biopsies with different lengths of recovery after transplantation we can potentially further improve our understanding of DGF, identify novel potential therapeutic targets in the donor or predict and appropriately tailor post-op management for transplant patients.
Approved by Steering Committee:6 April 2017
Feedback received:NO
RAP027: A proteomic approach to the identification of proteins associated with primary graft non-function after liver transplantation—pilot study
Shahid Farid
Overall survival after liver transplantation has significantly improved in recent years. However, early graft failure, termed primary non-function (PNF), remains a serious postoperative complication with high associated mortality and morbidity. The only treatment remains early re-transplantation but availability of grafts is a limiting factor. Determining the risk of PNF is currently based on clinical judgement of donor and recipient factors. We intend to undertake the first proteomic-based study in the UK of liver donor tissue prior to transplantation, comparing grafts with and without PNF to enable identification of potential diagnostic biomarkers to increase accuracy in prediction/prevention of PNF.
Approved by Steering Committee:25 January 2017
Feedback received:NO
RAP028: Differential expression of mitochondrial microRNA (MitomiRs) in the donor liver and implication for graft function
Shirin Khorsandi
The integrity and behaviour of mitochondria are recognised determinants of liver transplant outcome. MicroRNA are small fragments of non-coding, single-chained nucleic acids that define cell behaviour and function, by regulating gene expression. MicroRNA are found throughout the human body. MitomiRs are microRNA species that have been identified to localise to the mitochondria. The balance of microRNA relationships within and in between cells determines health and understanding this, and their associated cellular ramifications, will help to develop approaches to predict donor liver function as well as generate strategies that will protect the liver on reperfusion.
Approved by Steering Committee:19 June 2017
Feedback received:Results expected November 2019
RAP029: Donor liver endothelial glycocalyx and the outcome of liver transplantation
Farid Froghi
Organ donor shortage remains a major limitation in liver transplantation. This is partly mitigated by an increase in the use of extended criteria donor organs which are associated with more complications. In this study we aim to identify areas where damage to blood vessels occur during the organ donation process. This would then give us an opportunity to help devise strategies to prevent damage to vessels at the right time and improve the quality of the donated organs.
Approved by Steering Committee:15 March 2018
Feedback received:NO
RAP030: Circulating inflammatory factors in deceased organ donors result in innate immune activation
Todd Brennan
We hypothesise that brain-death of the deceased organ donor results in the release of specific Damage Associated Molecular Patterns (DAMPs) that activate the donor’s innate immune system and endothelium, resulting in graft inflammation and injury that predisposes transplanted donor organs to rejection. Our goal for this proposal is to identify these DAMPS and signalling pathways involved in the inflammatory response to brain death, and to characterise the activation of innate immune cells in deceased transplant donors. Identification of the donor-derived mediators of inflammation will allow for the development of specific interventions to reduce immune activation in transplant recipients by targeting inflammatory responses in the transplant donors. Our long-term goal is to develop interventions that increase the clinical success of solid-organ transplantation by reducing transplant rejection while minimising the risk of adverse effects of immunosuppression.
Approved by Steering Committee:14 August 2017
Feedback received:NO
RAP031: Investigation of BK viral immunity in health and disease in renal transplantation
Ciara Magee
BK virus (BKV) is a polyoma virus commonly found in the transplant population and is a rare but important cause of transplant failure in kidney transplant recipients. A high proportion of the general population (and therefore organ donors) have been exposed to the virus; little is known, however, about the types of virus present within the UK donor population, or the factors which result in some recipients developing progressive inflammation and transplant loss. This project aims to investigate the prevalence of various BKV subtypes in the UK donor population and thereafter to investigate factors influencing development of BK infection and kidney injury.
Approved by Steering Committee:31 August 2017
Feedback received:NO
RAP032: Assessment and significance of pancreatic steatosis in pancreas transplantation and its association with graft pancreatitis
Sham Dholakia
In 2016 there were almost 3,000 offers of whole organ pancreas for transplant which translated into only 200 transplants. A large proportion of these organs were discarded due to being too fatty. When fatty organs are implanted it is thought they promote inflammation and propagate pancreatitis, which adversely affects the recipient and their outcome. Being better able to quantify how fatty is too fatty is essential in not wasting large amounts of resources and organs but also in ensuring only the best organs are transplanted.
Approved by Steering Committee:28 December 2017
Feedback received:NO
RAP033: Investigation of myocardial gene expression in primary graft dysfunction by RNA sequencing
Aravinda Page
Heart transplantation is the best treatment for patients with severe heart failure. Unfortunately the demand for heart transplantation is greatly outstripped by the number of available hearts. In the UK only 27% of donor hearts end up being transplanted. A significant proportion are unused due to fears of poor function post-transplantation. However, even of the hearts that are used, a number are still faced with poor function post-operatively. This study aims at investigating measurable differences between good and bad hearts which can be tested to predict patient outcome.
Approved by Steering Committee:19 February 2018
Feedback received:NO
RAP034: The assessment of aspiration in donor lungs turned down for transplantation.
Jasvir Parmar
Lung transplantation remains the only option for many patients with advanced lung disease. Unfortunately, this life-changing procedure is limited by the number of available donor lungs. In the UK, only half of patients on the waiting list will receive a lung transplant after a year of waiting. A significant number of donor lungs that are offered are declined based on a subjective opinion related to the risk of aspiration and potential lung injury. We believe that the use of molecular markers of aspiration will provide a more objective yet accurate assessment and lead to more lungs being transplanted.
Approved by Steering Committee:15 March 2018
Feedback received:NO
RAP035: Assessing and optimising donation after cardiac death (DCD) liver grafts for transplantation
Eunice Lee
There are currently few objective methods of assessing whether a liver graft will function after transplant. A tissue marker to assess liver viability and risk of graft complications prior to implantation would be extremely helpful, to reduce transplant complications and the need for re-transplantation. The aim of this research is to define the molecular signatures of donation after cardiac death (DCD) and donation after brain death (DBD) livers that develop complications in comparison to livers that function well, in order to identify potential markers of viability.
Approved by Steering Committee:13 September 2018
Feedback received:NO
RAP036: Using an integrated proteomic, transcriptomic analysis and histology to identify molecular signatures of donor kidney quality
Maria Kaisar
Transplantation is the optimal treatment for end-stage kidney failure; however there is a limited supply of suitable organs and a need for better markers to inform the decision to transplant a kidney, whilst minimising patient risk and organ wastage. Currently, we use a scoring system based on how the kidney looks under a microscope, but we know that although this improves organ use, it still isn’t perfect. We want to identify markers that better predict how good a transplant will be. To do this, we will combine analysis using -omics technologies in kidney biopsies. We can then select a small number of markers that best associate with bad or good outcomes. We hope this will provide a way of optimising the use of organs for transplantation thereby maximising patient benefit.
Approved by Steering Committee:10 May 2018
Feedback received:NO
RAP038: Senescence as a potential therapeutic target for aged related cardiac dysfunction
Gavin Richardson
With age, the heart accumulates senescent cells, which don’t function in the way they should. These senescent cells produce substances that can make cells around them senescent or sick as well, thereby affecting the health of the heart as a whole. We now have evidence that drugs targeting these senescent cells and removing them from the system improve the health of old hearts. We aim to understand how these drugs work in greater detail in order to find ways to prevent or even reverse heart failure in the elderly.
Approved by Steering Committee:18 October 2019
Feedback expected:April 2021
RAP039: How does normothermic regional perfusion prevent the development of ischaemic cholangiopathy in DCD liver transplantation?
Hannah Esser
The utilisation of DCD organs is affected by ischaemia-related complications caused by the extended warm ischaemia time prior to cold storage. In the setting of DCD liver transplantation the main problem is the development of ischaemic cholangiopathy. Studies report decreased rates of ischaemic cholangiopathy following NRP. We hypothesise NRP prevents cholangiocytes from being driven into senescence resulting in less hepatic progenitor cell damage and improved tissue regeneration and repair. We aim to compare biopsies from DBDs, DCDs and NRP-DCDs. The comprehensive assessment of biological processes involved in NRP will possibly allow for improvements in outcomes and expansion of DCD-utilisation.
Approved by Steering Committee:14 June/4 September 2018
Feedback received:Results expected August 2022
RAP043: Validation of a transcriptional signature predictive of one-year graft function in deceased circulatory death kidney transplants
Menna Clatworthy
Transplantation is the best treatment for kidney failure but there is a limited supply of suitable organs. Currently, we use a scoring system based on how the kidney looks under a microscope to help decide whether a kidney will have good function, but this test isn’t perfect. We have identified genetic markers present in kidney biopsies that we think will better predict how well a transplant will function in the long term. We now want to test and confirm this, by measuring these markers in n=1000 samples so that we can be sure that it will be a useful test that can be rolled out into clinical practice.
Approved by Steering Committee:22 October 2018
Feedback received:NO
RAP044: Predictive biomarkers for quality of the donor pancreas and viability of its islets
Fenna van de Leemkolk
Current clinical parameters to assess quality and predict viability of DBD/DCD pancreases (either as solid organ or islet transplantation) lack specificity and granularity. The aim of this project is to investigate whether the biomarkers microRNA-375, microRNA-200c and unmethylated cell-free DNA-INS, which have been shown to reflect cell damage of the islet β-cell, are associated with islet yield and function after isolation as well as solid pancreas graft function at one year. To increase organ utilisation, better insight into mechanisms of injury and repair is necessary. Identification of clinically relevant biomarkers may help the clinical decision to transplant.
Approved by Steering Committee:7 May 2019
Feedback expected:February 2020
RAP049: Investigating the correlation between donor kidney histology and cortical microcirculation through the use of intra-operative infrared thermography during implantation
Dilan Dabare
There are no imaging modalities to assess the effects of ischaemia-reperfusion injury on the microcirculation during kidney transplantation. Infrared thermography (IRT) is a non-invasive modality which captures the thermal radiation emitted by kidneys as a result of capillary blood flow and therefore provides an ideal method to assess the microcirculation. Our preliminary imaging of kidneys during implantation has revealed that the heterogeneity of thermal radiation correlates with delayed graft function. This study will evaluate how the pre-existing morphology of the kidney correlates with IRT parameters at reperfusion and compare the predictive value of IRT with histology scores on early graft function.
Approved by Steering Committee:25 January 2019
Feedback expected:December 2019
RAP051: Evaluating the impact of catabolic biological processes in the deceased donor kidneys
Rebecca Vaughan
Kidney transplantation is the best treatment for end stage kidney disease but transplants only rarely last the lifetime of the recipient. Approximately 840 kidney recipients go back to dialysis every year in the UK. This is distressing for both the patients and their families, having to face the limited prospects for a second transplant. To date, we do not have a clear understanding of the factors that make transplants stop working after transplantation. However, we know that deceased donor kidneys that work well in the donor are more likely to last for a longer time in the recipients. The challenge is that, in an ageing population, more kidneys are being offered from older donors, many of whom have age-related diseases such as obesity, diabetes or cardiovascular disease, to meet the increasing demand. These kidneys tend to perform less well after transplant with an increased likelihood of recipients having to return more quickly to dialysis.
We have previously identified that kidneys that perform poorly after transplant undergo biological processes that cause certain proteins within the kidney, essential to maintain a good function, to break down. Our proposed work aims to 1) better understand what causes degradation to kidney cytoskeletal proteins and 2) to describe the endogenous proteases that are activated during brain death and circulatory arrest and lead to cytoskeletal changes that may impact the long term function post-transplant. The translational value of this proposal is that protein fragments that are generated from cytoskeletal protein degradation may have diagnostic value. In addition, this research work will provide an insight of potential targets for intervention during donor management or kidney preservation to block these processes.
Approved by Steering Committee:19 June 2019
Feedback expected:December 2020
RAP052: A predictive molecular signature of Primary Non Function (PNF) in the kidney graft: a proof of concept study
Fenna van de Leemkolk
Primary Non Function (PNF) is a catastrophic outcome of kidney transplantation. As a consequence, many kidney grafts with an anticipated risk of PNF are declined for transplantation thus compromising the donor pool. For this reason, a biomarker signature in DBD and DCD donor serum and urine predicting future PNF would be of great potential value to give sufficient guidance to clinicians with regards to their decision whether to accept or decline a (marginal) kidney. If this molecular signature can be identified, it may reduce the incidence of PNF and allow expansion of the donor pool, increasing organ utilisation.
Approved by Steering Committee:19 June 2019
Feedback expected:March 2020
RAP053: The search for novel biomarkers of hypertension
Alex Paterson
It is well known that patients with donated organs from those with high blood pressure exhibit a lower survival rate. This present study aims to see if novel changes taking place in the blood can help to identify those that have a higher blood pressure. This would enable improved screening of post-mortem donors, where it is no longer possible to measure blood pressure, for markers associated with chronically elevated blood pressure. Furthermore, this study is also looking towards prognostic changes that occur before the onset of high blood pressure. This would allow for treatment plans to be put in place prior to blood pressure rising and putting strain on internal organs.
Approved by Steering Committee:5 April 2019
Feedback expected:December 2019
RAP055: Evaluation of Hypothermic Oxygenated Perfusion (HOP) ex-vivo heart perfusion to expand the donor pool and improve transplant outcomes
Lu Wang
Many hearts offered for transplant are not used due to concern about how well they may work following a period of preservation on ice. This project aims to compare machine perfusion with blood at low temperature, with the traditional preservation method with an icebox. We hope to be able to, prior to transplantation,
1) extend the preservation duration
2) develop tests to assess heart health
3) extend these investigations to the hearts donated after circulatory death (known as DCD donors) for transplantation. This project will potentially improve safety and increase the number of hearts available for transplant.
Approved by Steering Committee:31 October 2019
Feedback expected:May 2021
RAP056: Pilot genotyping study for QUOD Whole Organ atlases
Anna Gloyn
The MRC-funded QUOD expansion includes the development of whole organ pathology atlases, incorporating rich data from genomic, transcriptomic and proteomic studies. With the first pancreata having been received and scored in Newcastle, we are ready to begin genotyping these donors. We would like to begin by using spleen samples to genotype the first donors. We would prefer not to use the pancreas tissue due to the difficulty of extracting high-quality RNA and DNA from the pancreatic tissue, as well as the need to reserve pancreatic tissue samples for targeted single-cell RNA Seq studies.
Approved by Steering Committee:28 June 2019
Feedback expected:March 2021
RAP057: Investigation of BK viral immunity in health and disease in renal transplantation
Stephanie Chong
BK virus (BKV) is a polyoma virus commonly found in the transplant population, and is a rare but important cause of transplant failure in kidney transplant recipients. A high proportion of the general population (and therefore organ donors) have been exposed to the virus; little is known, however, about the types of virus present within the UK donor population, or the factors which result in some recipients developing progressive inflammation and transplant loss. This project aims to investigate the prevalence of various BKV subtypes in the UK donor population and thereafter to investigate factors influencing development of BK infection and kidney injury.
Approved by Steering Committee:23 August 2019
Feedback expected:August 2022
RAP058: Non-invasive biomarkers of early renal allograft function
Katie Connor
The shortage of organs available for donation has resulted in the increased use of organs from deceased donors. These kidneys endure a relatively longer period without an adequate blood supply and subsequently become injured (ischaemia reperfusion injury (IRI)). IRI is associated with reduced function of the transplanted kidney following transplantation. We have found that levels of small molecules called microRNAs vary in kidneys undergoing experimental IRI. We now plan to measure microRNAs in donor samples to see if we can predict early graft function after transplantation with the hope this could potentially increase the number of organs available for transplantation in future.
Approved by Steering Committee:23 August 2019
Feedback expected:November 2020
RAP059: MicroRNA-709 mediates acute tubular injury in recipients post renal transplantation through its effects on mitochondrial function
Daniel-Clement Osei-Bordom
The project will look at mitochondrial injury markers in cadaveric kidneys with acute kidney injury (AKI). About 20% of kidneys that are offered for transplant have a degree of AKI and at present attempting to identify which donor cadaveric kidneys will recover from AKI and which kidneys will not is an inexact science. We aim to identify kidneys that have developed AKI and to quantify how much damage is AKI and how much is permanent, using quantification assays and measuring upregulation of microRNA-709, which is a known marker of mitochondrial dysfunction in proximal convoluted tubule (PTC) cells and correlates well with degree of AKI. This is based on a cell line model and also on kidney biopsy tissue from patients with largely drug-induced AKI. We want to see if if miRNA-709, along with other mitochondrial markers, correlates well with the grade of AKI in donors who on the whole have AKI of ischaemic aetiology. It would be of clinical benefit to patients to identify if there are any markers which can predict which of the AKI kidneys will recover good function and which will not.
Approved by Steering Committee:31 October 2019
Feedback expected:February 2020