The following projects have been reviewed and approved by the QUOD Steering Committee.
Do you have a status update for us? Want to submit your Part C Form? Please email quod-research@nds.ox.ac.uk to let us know.
- RAP109: Validation of molecular profiles of donor kidney quality
Letizia Lo Faro
The transplant community needs tools to assess organs donated for transplant. These tools are necessary to help predict how the organs will function and whether they can benefit from therapeutic interventions before transplant. In our previous work we have found molecules (proteins) in donated kidneys that are associated with poor outcomes (poor function) following transplantation. We now want to validate these associations in a larger group of samples. Using clinical samples collected in QUOD, we will study whether our proteins of interest are associated with poor kidney outcomes, specifically in the case of kidneys donated from more injured donors.
Approved by Steering Committee: April 2024 - RAP106: Recurrent IgA nephropathy post kidney transplantation
Vivienne Ralph
Some conditions which affect our own kidneys such as IgA nephropathy can also affect the transplanted kidney and can cause it to stop working. We know how IgA nephropathy affects our kidneys but we do not completely understand how IgA nephropathy occurs in the transplanted kidney and so currently, there are no effective treatments for this. By testing patient blood and kidney tissue this will allow us to predict whether treatments currently being developed for IgA nephropathy in our own kidneys will be beneficial to treat IgA nephropathy in the transplanted kidney.
Approved by Steering Committee: May 2024 - RAP103: Pulsatio – aiming to trigger rejection in cardiac tissue and use ML to analyse associated biomarkers to create a model of post-transplant cardiac rejection
Santorini Scientific Ltd
Pulsatio seeks to improve quality of life for cardiac transplant patients by addressing the challenge of post-transplant rejection. The project builds upon previous research on creating a bioprinted heart tissue and seeks to develop a platform for testing rejection management strategies. The current method for treating rejection is immunosuppressant drug therapy, which has severe side-effects. This project aims to characterise tissue viability over time and cause rejection-like responses for testing novel therapeutic therapies. It will also extend the lifespan of in vitro tissue models and contribute to more accurate pre-clinical testing, reducing the reliance on animal models.
Approved by Steering Committee: February 2024 - RAP102: Understanding the histological changes of livers undergoing normothermic machine perfusion
Christopher Watson
Ex situ normothermic machine perfusion (NMP) of the liver is a novel technique for preserving and assessing a liver before it is transplanted. There are currently no studies of the microscopic effect of NMP on the liver. By looking at liver biopsies from deceased donors, and those taken during NMP as part of a separate study, we hope to be able to characterise the changes.
Approved by Steering Committee: December 2023
RAP101: Unravelling the tissue-specific geography of protein aggregation in human disease
Nicola Dyson
Aggregation of the peptide hIAPP in the pancreas is thought to be involved in dysfunction and loss of insulin-producing beta-cells in the development of type 2 diabetes. This project will explore where aggregation happens in context to the pancreas tissue geography and how it interacts with other tissue components. We will investigate the structure of hIAPP aggregates and whether different forms of these are found in specific areas and in individuals with and without diabetes. hIAPP is also secreted into the bloodstream so we wish to look at whether the amount and form of peptide is different in these individuals.
Approved by Steering Committee: December 2023
RAP100: Examine the mechanisms in the potential downregulation of brain stem death induced proinflamatory responses by simvastatin
Jenny Gilmour
Despite being the most widely used form of donation, donation after brain stem death is associated with inflammatory processes and organ damage which can negatively affect organ function in the recipient. Drugs called statins have been shown to reduce inflammation across a range of illnesses. Research has also shown benefits in recipients who received organs from donors treated with statin as part of the donor management protocol. We therefore aim to assess whether statin treatment in the donor has any effect on global and tissue inflammation and explore the underlying mechanistic pathways that confer statin induced organ protection.
Approved by Steering Committee: January 2024 - RAP099: Comparison of gene expression between donors undergoing normothermic regional perfusion and those DCD and DBD donors undergoing traditional organ recovery
Chris Watson
Normothermic regional perfusion (NRP) is a novel technique used when removing organs from donors who have died following circulatory death. It has been associated with superior outcomes for kidneys and livers compared to traditional DCD recovery. Our study will compare gene expression in organs from donors that have undergone NRP with those undergoing traditional organ retrieval methods and will try to determine why NRP appears to be so good.
Approved by Steering Committee: December 2023 - RAP097: Pilot study of discarded human pancreas assessment
Mohamed Elzawahry
More than 60 million people worldwide suffer from type 1 diabetes, and pancreas transplantation is one of the most effective treatments. However, there is a shortage of suitable donor organs and in the UK about 50% of pancreases retrieved for transplant are not used because of concern about organ quality. So, developing objective measures of assessment is a priority. We plan to use MRI scanning combined with a technique called machine perfusion to assess pancreases. This technique enables organ assessment for injury, repair, viability and possible introduction of novel therapies. This research can increase organ utilisation and improve outcomes after transplantation.
Approved by Steering Committee: April 2023 - RAP096: Characterisation and evaluation of potential hepatitis B virus transmission risk in anti-HBc positive liver donors
Peter Simmonds
In blood transfusion and transplant, there have been many cases of hepatitis B virus (HBV) transmission where virus levels are very low in the blood and infection cannot be detected by normal donor screening. This is termed occult (hidden) hepatitis B virus infection, which is important for transplant safety. We will investigate how these low-level but active infections of the liver can be detected, including the presence of replicating forms of HBV DNA in the liver and potentially new biomarkers indicating active host responses to infection. This would lead to increasing liver availability where active HBV DNA is undetectable.
Approved by Steering Committee: June 2023 - RAP095: Identifying older donor hearts suitable for transplantation: the use of senescence as a marker of biological age
Gavin Richardson
For patients with end-stage heart failure (HF), transplantation can be effective, though we face the problem of insufficient donor hearts to meet demand. Cardiac dysfunction and HF are associated with ageing, and this has led to recommendations that only young hearts should be used for transplants and thus older healthy hearts, which may be more suitable for transplant than some young hearts, are turned down. We suggest that by exploiting the association between senescence, biological myocardial ageing, myocardial remodelling, and cardiac dysfunction, we will identify a panel of novel biomarkers that indicate the suitability of donor hearts for transplantation, allowing for expansion of the donor pool while providing better assays to diagnose or predict HF in the ageing population.
Approved by Steering Committee: April 2023 - RAP094: Normothermic machine perfusion of discarded human kidneys following static cold storage to determine efficacy of ARGX-117 to block downstream molecular events leading to kidney damage
John Fallon
In renal transplantation upon reperfusion of the organ with warm oxygenated blood a damaging phenomenon occurs called ischaemia–reperfusion injury. A component of this injury is caused by activation of part of our immune system known as the complement system. Argx-117 is a compound which binds to a protein early in activation cascade inhibiting its action and is intended to limit the downstream immune activation. We aim to test the drugs in human kidneys that were deemed unsuitable for clinical transplantation on a machine perfusion device which aims to recreate the physiological process the kidneys are exposed to during implantation.
Approved by Steering Committee: January 2023 - RAP093: Investigation of the effects of normothermic regional perfusion on mitochondrial injury pathways and repair
Georg Ebeling
Transplantation is the definitive treatment for end-stage organ failure. As organ shortages persist, higher-risk donor organs, such as those from patients after circulatory death, are increasingly accepted. To improve the organ quality, retrieval surgeons use a novel technique to maintain isolated blood circulation in the donor prior to cold perfusion called normothermic regional perfusion (NRP). It remains unknown the extent by which this reduces tissue damage. We aim to investigate the effects of NRP on renal and liver mitochondria acting as an indicator of organ damage, to assess the role of NRP in potentially reducing organ injury and complications.
Approved by Steering Committee: December 2022 - RAP090: Cell death pathways activation in donor kidneys and associations with transplant outcomes
Lente Lerink
Cell death is a process involved in both health and disease. In the context of disease, it has recently gained interest as a target to limit damage. Also in the kidney transplantation setting, where cell death may occur in donor kidneys before implantation, it may be beneficial to intervene to minimise cell death. In this study, we will examine whether and which different cell death pathways are activated in different types of donor kidneys prior to transplantation, and if this affects transplant outcomes. This knowledge will contribute to a better understanding of cell death in the context of kidney donation and transplantation.
Approved by Steering Committee: August 2022 - RAP088: Investigation of transcriptional signatures predictive of suboptimal short and long-term outcomes in deceased brainstem 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 minimizing patient risk and organ wastage. Currently, we use a scoring system based on how the kidney looks like under a microscope, but we know that although this improves organ use, it still is not 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: October 2022 - RAP087: Complement activation during brain death
Laura Knijff
Many (patho-) physiological changes occur during brain death (BD) including the release of cytokines, hormones and changes in blood pressure. BD has been shown to be hostile, affecting transplantation outcomes. At the same time, several studies have shown that the negative effect of a prolonged period of BD on organ outcome can be reduced when applying optimised donor management. The complement system is part of the immune system and has been shown to be already activated in the donor. However, the time course of complement activation during BD is unknown. Several therapies inhibiting the complement cascade are currently in development. By characterising complement activation, we will determine the best time point to intervene and ultimately help improve transplant outcomes.
Approved by Steering Committee: August 2022 - RAP085: Investigating molecular changes to DCD kidneys associated to extended periods of warm ischaemia
Rebecca Vaughan
In the UK, the expectant wait time for a donor kidney is two-years, yet deceased after circulatory death (DCD) donors remain an under utilised source of donor organs. The DCD donation pathway involves an extended period of warm ischaemia (WI), which is associated to increased incidences of delayed graft function and primary non function posttransplant. The biological alterations triggered during WI and the impact on posttransplant function are not well understood, therefore this study will use a transcriptomics analysis to investigate molecular changes in DCD donor kidneys that correlate with increased length of WI and poorer functional outcomes at 12 months.
Approved by Steering Committee: August 2022 - RAP084: Evaluation of protein phosphorylation in kidney and liver biopsies from DCD and DBD donors by shotgun phosphoproteomics
Sadr ul Shaheed
Protein phosphorylation, a Post-translational modification on proteins, controls a large number of biological functions and also plays a pivotal role in a variety of important signalling pathways and linked to a wide spectrum of diseases. Qualitative and quantitative analyses of phosphorylation is useful for biomarker and mechanistic research and is an integral part of the characterisation of kinases biopharmaceuticals. Functional profiling of the phosphoproteome during kidney and liver transplantation is therefore of great biological significance and is likely to lead to the identification of novel targets for drug discovery and provide a basis for novel therapeutic strategies.
Approved by Steering Committee: October 2022 - RAP083: Assessing donor kidneys and monitoring transplant recipients (ADMIRE)
Maria Kaisar
We propose to evaluate discarded human kidneys to provide key information on associating MRI with morphological 3D histological changes and molecular profiling of kidney tissue. The vision for the future clinical pathway is that MRI can be developed to detect subclinical changes related to kidney injury. Such a tool could be applied to monitor the function of transplants and detect the return of kidney disease. We propose whole organ imaging and integration with 3D-histology and molecular profiling to develop a “short” MRI protocol that can be used to assess donor kidneys and monitor transplant graft function for early diagnosis and early treatments of kidney graft dysfunction. Replacing clinical biopsy diagnosis with non-invasive easily accessible imaging technologies we will improve the quality of life of patients.
Approved by Steering Committee: April 2022 - RAP082: Investigating the effects of brain death on mitochondrial function
Letizia Lo Faro
Donation after brain death (DBD) is one of the main sources of abdominal organs for transplant. Organs from brain dead donors present several cellular and molecular changes which can affect their quality and function post-transplant. Mitochondria, intracellular organelles modulating many cellular pathways, are negatively affected by brain death both in their function and structure. However, it is currently still unclear through which mediators brain death affects mitochondrial function and how. The aim of the present project is to study the effects of plasma from DBD donors on mitochondria in cell culture models, in order to characterise in more details the effects of brain death on mitochondria.
Approved by Steering Committee: May 2022 - RAP080: A novel, point-of-care, multi-analyte device for the detection of inflammation in deceased organ donors and its impact on transplant recipient outcomes
Nina Dempsey
Organ transplantation often involves the donation of organs by deceased donors. A degree of damage can occur to donor organs due to the underlying mechanisms leading to death in which there is widespread release of inflammatory molecules. This could affect how well the transplanted organs function in the recipient. We aim to analyse key inflammatory molecules in deceased donors using our newly developed, electrochemical, point-of-care inflammatory sensor and validate the accuracy of this sensor against gold standard, lengthy, reference test methods (Luminex). In doing so, we aim to determine whether the donor inflammatory profile ultimately influences outcome in transplant recipients.
Approved by Steering Committee: April 2022 - RAP078: Biosignature for kidney transplant failure – making kidney transplants safer
Sofia Ferreira Gonzalez
Cellular senescence, a status of irreversible proliferative arrest, is an important pathway involved in renal disease and has been suggested to also account for compromised graft function in the setting of kidney transplantation (Mylonas et al., 2021). Proteins characteristic for cellular senescence have recently been shown to be detectable in urine (Chen et al., 2017). In this project we want to assess the predictive value of cellular senescence components in donor urine for identifying kidney grafts with impaired post-operative function.
Approved by Steering Committee: April 2022 - RAP076: NRP retrieval: a chance of recovery for DCD kidneys
Rachel Thomas
Demand for kidney transplants exceeds supply so researchers investigate ways to safely utilise marginal kidneys that would previously have been rejected. Normothermic Regional Perfusion (NRP) is a novel retrieval technique that has the potential to increase the utilisation of livers from donors after cardiac death (DCD). The outcome for kidneys retrieved by NRP is less well established. It is hypothesised that NRP DCD kidneys will perform better in recipients than standard DCD organs and will have evidence of cellular recovery. We propose an innovative analysis to investigate whether NRP has an impact on the molecular recovery.
Approved by Steering Committee: March 2022 - RAP072: The role of immune complexes in vaccine-induced thrombosis and thrombocytopenia
Rebecca Shaw
Immune complexes play an important role in the syndrome heparin-induced thrombocytopenia (HIT) which occurs in some patients after heparin administration. In this work, we will demonstrate that the immune complexes exist within the circulation of patients with vaccine-induced thrombosis and thrombocytopenia (VITT), without prior exposure to heparin.
Approved by Steering Committee: July 2021 - RAP071: Understanding the cardiac senescent environment in vivo
Georgina Ellison-Hughes
The human heart displays regenerative potential. Newly formed, proliferating cardiomyocytes have been detected in the heart, and as the heart ages, senescent cells (that are withdrawn from the cell cycle and abnormal) accumulate contributing to cardiac regenerative deterioration. This research project aims to extract the proliferating and senescent cardiomyocytes from the hearts of different aged donors (>5 years) by laser microdissection followed by in-depth multi-omic profiling. We envision that the scientific information gained from this research will help design optimal protocols for prevention of cardiac deterioration with ageing/disease, and regeneration of heart tissue to treat heart diseases and failure.
Approved by Steering Committee: June 2021 - RAP070: Apolopoprotein L1 in people of African ancestry living in the UK: Exploration of genetic and environmental factors associated with Chronic Kidney Disease (APPLE-CKD study)
Kate Bramham
People of African ancestry have 3–5 fold higher rates of chronic kidney disease (CKD). Mutations in the apolipoprotein-L1 gene are present in many people of African ancestry with CKD and appear to protect against sleeping-sickness. However, some people have these mutations, but do not have kidney disease. We propose to compare molecular changes in specific parts of APOL1 genes which may lead them being ‘switched-on’. We will study blood/spleen and kidney samples from CKD patients and QUOD controls. The findings will help us to understand how APOL1 disease develops and may identify people with APOL1 mutations at risk of CKD.
Approved by Steering Committee: June 2021 - RAP069: Investigation of necroptosis in transplanted and diseased kidneys
Genentech
During kidney transplantation, interruption and restoration of blood flow to the transplanted kidney that naturally occurs during procurement, transport, and surgical implantation unavoidably causes a certain amount of injury to the kidney. This kidney injury, if severe enough, can then lead to poor outcomes after transplant such as a prolonged requirement for dialysis or reduced long-term function or longevity of the transplanted kidney. A biochemical mechanism called “necroptosis” may be involved in this process. By studying necroptosis in biopsies from transplanted kidneys, we may identify specific molecular targets that if blocked might improve long-term outcomes.
Approved by Steering Committee: February 2022 - RAP067:PIEZ01 in liver regeneration: activation in scenarios of small for size syndrome and changes in portal vein flow and variations in different ethnic backgrounds
Ahmed Ghoneima
This research project aims to understand the role of a recently-identified protein (PIEZO1) in liver injury and regeneration. Surgeries performed in the liver for cancer and transplantation can lead to changes in blood flow and blood pressure within the liver. Recent research on PIEZO1 has demonstrated its presence and activity in the liver vascular walls as well as its response to the friction forces caused by changes in blood flow. The understanding of PIEZO1 function in liver vasculature adaptation to blood flow changes after surgeries and on liver regeneration. In addition, the recent recognition of ethnic differences in mutations with PIEZO1 and its impact on susceptibility to SARS-Cov-2 infection raises an intriguing possibility of similar differences effecting PIEZO1 activation in liver with potentially different physiological responses that may be detrimental to clinical outcomes.
Approved by Steering Committee: August 2020 - RAP066: Understanding Covid-10 impact on kidney, liver and spleen
Gabriel Oniscu
In order to understand the changes at individual organ level (liver, kidney, spleen) in patients who died as a result of Covid-19 infection, we aim to compare the pathological findings from post mortem investigations with healthy tissue stored in QUOD biobank from a matched cohort of samples from the pre-Covid era.
Approved by Steering Committee: August 2020 - RAP064: Identification of an RNA signature for early liver allograft function
Chris Watson
Following transplantation some donor livers work very well and some poorly, while a few (3%) fail to work at all. This study will look at a selection of livers, with some that worked very well and some that worked poorly. By looking at genetic markers in the liver cells we hope to be able to identify processes that are characteristic of good and bad livers. These will help us to define and target possible treatments for livers before transplantation to ensure good immediate function.
Approved by Steering Committee: July 2020 - RAP065: Elucidating the role of senescence in NAFLD and cardiometabolic disease
Eilidh Livingstone
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury, and is diagnosed by an invasive liver biopsy. During NAFLD, fat accumulates in the liver and fibrosis or cancer may develop. The mechanisms underlying NAFLD progression are not well defined. After damage, cells may enter a state of senescence, preventing cell division. Senescent cells also produce signals which trigger inflammation and spread senescence across the tissue. Senescence correlates with NAFLD progression, and adverse outcomes from kidney transplantation. This project aims to identify senescent factors which may lead to novel therapeutic or improved diagnostic tools.
Approved by Steering Committee: August 2020 - RAP063: Integrating clinical features, histology, SNP genotypes, RNA sequencing from steatotic donor livers to identify predictors of transplantation outcomes using machine learning
Hussain Abbas
The success of liver transplantation is critically limited by waiting list deaths. Therefore donor shortages necessitate the need to maximise the use of high-risk fatty livers; however, methods of estimating their fat content are not well validated. A clinical-risk score will enable greater identification of high-risk organs associated with poor outcomes. Application of machine learning founded on gene analysis, digital tissue imaging and blood tests will facilitate identification of biomarkers and allow optimisation those organs that are predicted to have poor outcomes. This will enable targeted intervention to be delivered during normothermic organ preservation outside the body prior to transplantation.
Approved by Steering Committee: January 2020 - RAP061: EvoGnostic
Evotec
Within several disease areas, the aim of our project is to use multi-omics to identify novel pathomechanisms including those that are relevant for poor outcome of transplantation events and drug targets, to improve patient stratification of clinical trials, and to establish novel and more sensitive diagnostic and prognostic biomarker to improve patient care. To this end we are performing Bulk RNASEQ, Proteomic, and Metabolomic analysis of human samples. We combine this OMICs fingerprint with clinical information to define healthy and disease state signatures. QUOD biopsies will be instrumental to establish healthy state signatures, including the influence of age, health status, and medication.
Approved by Steering Committee: July 2020 - RAP060: Assessing the impact of pre-existing senescent cells on transplant outcomes
David Ferenbach
There is a major need for novel treatments to prolong kidney transplant survival. There is evidence that levels of senescent (permanently growth arrested) cells rise in deteriorating kidney transplants – and exciting work in other organs shows that killing these cells, can retard organ scarring and prolong healthy lifespan. Senescent cells accumulate with age, and kidneys from old donors have inferior outcomes to those from the young. This project will quantify levels of senescent cells in young and old kidney donors – and test the correlation between baseline senescence, delayed graft function and longer term graft outcomes.
Approved by Steering Committee: December 2019 - 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: October 2019 - 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: August 2019 - 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: October 2019 - 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: June 2019 - 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: April 2019 - RAP052: A predictive molecular signature of primary non function 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: June 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: June 2019 - RAP049: Investigating the correlation between donor kidney histology and cortical microcirculation through the use of intraoperative 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: January 2019 - 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: May 2019 - RAP042: Is there a difference in the serum protein network reflecting a cerebral injury between donation after circulatory death donors who proceed to donation and those who do not?
Kasia Bera
Donation after circulatory death (DCD) is an important source of deceased organs for transplantation in the UK. Part of this process is identification of patients who are likely to die within an acceptable warm ischaemia time, following the withdrawal of life support. This identification is currently based on expert judgement. We propose that there may be quantifiable biomarkers related to measuring the degree of associated brain injury in those patients who go on to successfully donate via DCD. This may be useful in prognostication of timely death; improving organ recovery rates, reducing unnecessary distress for families of unsuccessful donors, and improving clinician confidence in decision making.
Approved by Steering Committee: July 2022 - 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: September 2018 - 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: October 2019 - 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: May 2018 - RAP035: Assessing and optimising donation after cardiac death 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: September 2018 - 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: March 2018 - 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: February 2018 - 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: December 2017 - 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: August 2017 - 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: August 2017 - 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: March 2018 - 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: June 2017 - 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 January 2017 - 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: April 2017 - 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: December 2017 - 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: April 2017 - 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: November 2016 - 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: July 2016 - 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: April 2016 - 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: May 2016 - 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: July 2016 - 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: November 2015 - 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 October 2015 - 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: November 2015 - 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: August 2015 - RAP010: Investigation of the mechanisms of injury and stress response in kidneys from DBD donors: correlation with delayed graft function vs immediate function
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 delayed graft function (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 immediate function). Once validated, these profiles can provide a useful tool for the correct assessment of organ quality.
Approved by Steering Committee: July 2015 - RAP009: Method optimisation as a prelude study of proteomic and microRNA analysis of laser capture micro dissected proximal tubules obtained from DBD kidney biopsies (delayed graft function vs immediate function)
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 delayed graft function vs immediate function 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 laser capture micro 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: May 2015 - 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: April 2016 - RAP003/004: Investigation of injury pathways and mitochondrial bioenergetics in kidneys and livers after brain and circulatory death
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: August 2015 - 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: August 2015 - 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: June 2015