Dr Maria Kaisar – Developing new ways to assess kidneys so transplants last for longer.

With funding from Kidney Research UK, a team of researchers from the University of Oxford, the University of Nottingham and University College London will develop ways to assess donor kidneys and predict how well they will work after transplant.

Having a kidney transplant is the best treatment for kidney failure, but the demand for donated kidneys is high.

To save more lives, doctors are now accepting kidneys from older or higher risk donors. These kidneys may also work less well after transplantation. This can have devastating effects, causing patients once recovering from transplantation to also go back on to dialysis, and wait for another transplant.

Right now, doctors cannot accurately assess donor kidneys. This makes it difficult to predict how well a transplant will work and how long a kidney will last after it has been transplanted.

Thanks to Kidney Research UK’s grant award of £237,626, (in partnership with the Stoneygate Trust), the ADMIRE study ‘Assessing Donor kidneys and Monitoring Transplant Recipients’ aims to address this clinical challenge.

Dr Maria Kaisar

Dr Maria Kaisar from Oxford University’s Nuffield Department of Surgical Sciences (NDS) is the Principal Investigator on the study and leads a team of co-investigators from NDS (Professor Rutger Ploeg, Dr Edward Sharples, Mr Simon KnightMr James Hunter and Dr Sadr Shaheed), the Oxford Big Data Institute (Dr Alberto Santos Delgado and Dr Philip Charles) and the Radcliffe Department of Medicine (Dr Elizabeth Tunnicliffe)

Dr Maria Kaisar and her team will utilise the Oxford Transplant Biobank (OTB) and the Quality in Organ Donation (QUOD) biobank to look for marker proteins in the donors’ blood samples. They use these samples to develop a mathematical model to predict how well donor kidneys will work after transplantation. The successful model would allow doctors to accurately assess kidneys and only transplant those that will function well. It could also identify suitable kidneys previously deemed too high risk to transplant.

With Professors Sue Francis and David Long from the University of Nottingham and University College London, the NDS team will use the QUOD X platform to also develop a monitoring strategy. MRI scanning methods will be performed on both the donor organ before it is transplanted, and later on after transplantation. This will allow us to monitor how well the transplanted organ is functioning.

“I am absolutely delighted that our study received this funding award by Kidney Research UK in partnership with The Stoneygate Trust,” said Maria. “This funding will enable us to bring scientific and clinical expertise together in collaboration, to develop novel non-invasive methods to better assess donor kidneys and, predict how well a transplant will work in the recipient. We also envisage that our planned scientific work will offer many opportunities to our early career scientists, to further develop their skills and research expertise in studying kidney disease. “

Letizia Lo Faro – Use of QUOD samples in research ‘Case Study’

My name is Letizia Lo Faro and I am a Post-Doctoral research scientist in the Oxford Transplant research group. I have so far used QUOD samples in 4 or 5 separate research studies. In one of these, conducted together with Ms Flavia Neri (University of Padova), we were interested in studying the molecular features of donor kidneys with acute kidney injury (AKI) having different functional outcomes after transplant.

Letizia Lo Faro

Once we fully characterised our research question, we moved onto donor sample selection. We decided to compare 4 different groups of donors: with or without AKI and each with good (≥45 mL/min) or poor (<45 mL/min) function (eGFR) 12 months post-transplant, for a total of 40 donors. We maximised the difference between outcomes as much as possible and to allow for fair comparisons we decided to match the groups for several other variables (donor age and gender, BMI, cold ischaemia time, recipient age, recipient gender…just to name a few). I believe appropriate sample selection is a key step in such retrospective studies and we engaged with the QUOD Data Manager earlier on in the process. This provided us with a great overview of all the variables available and also made sure our groups were nicely balanced.

Once we were happy with the donor selection, we proceeded with requesting the samples from the biobank. In this case they were full RNAlater frozen kidney biopsies and formalin-fixed paraffin-embedded (FFPE) kidney tissue slides. In this study we were interested in studying protein expression, so first of all we processed the tissue biopsies to mechanically homogenise them and extract the proteins. Later on the proteins were quantified and the expression of 17 proteins of interest was analysed by Western Blotting (a technique where a mixture of proteins is separated on a gel, based on the molecular weight, and, following transfer on a membrane, proteins of interest are identified by binding to specific antibodies). Results were then analysed with statistical tools.

A set of FFPE slides was then utilised for histological assessment, by standard staining with haematoxylin and eosin (H&E), to quantify chronic and acute tissue damage. One additional set of slides was utilised for confirmation of the western blotting results by immunohistochemistry, another method which allows to check for the presence of certain proteins/products in a tissue, by binding with labelled antibodies.

Results from this study were presented at the British Transplantation Society meeting last year and we are currently finalising a manuscript for publication.

Our results suggested that specific molecular patterns are recognizable in acutely inured kidneys that proceed towards worse function after transplantation. In particular, Peroxisome proliferator-activated receptor gamma (PPAR gamma) specifically increased after acute injury that progressed to worse function, underlining a potential role of metabolic dysfunction in the development of kidney disease (Figure 1).

Figure 1. The protein PPARg, quantified by western blotting analysis, is significantly increased in AKI kidneys with poor outcomes 12months post-transplant.

Our findings have helped identify potential molecular mechanisms involved in the progression of acute kidney injury to chronic kidney disease and post-transplant dysfunction and may constitute a therapeutic target of further interventions aimed at improving the quality of donated kidneys with an acute injury.

Working with QUOD samples has allowed us to really dive deep into the study of molecular mechanisms of kidney injury and the availability of different sample types also allowed us to apply various techniques and methods to validate our findings.

COVID BioArchive Update

Since March 2020 the QUOD team has been supporting the national effort in the fight against COVID-19. QUOD’s extensive biobanking expertise, infrastructure and personnel have served to set up the NHSBT Oxford COVID BioArchive (COBA).  Over 68,000 blood samples from convalescent plasma donors who have recovered from COVID-19 have been collected and processed as part of the NHSBT Convalescent Plasma programme. In addition, since September COBA has received over 18,000 samples collected from recipients of convalescent plasma and monoclonal antibody treatment in the international RECOVERY trial.

These samples were used by a number of research groups, NHSBT and Public Health England in a variety of projects, including assessment of novel COVID-19 tests, characterisation of COVID-19 antibody function, and analysis of the efficacy of convalescent plasma treatment. With this COVID BioArchive, we have been able to establish a robust and sustainable resource for future validation and research helping us to gain better insight into COVID-19 and anticipate targeted intervention.

You may have heard that on 15th January randomisations of patients into convalescent plasma was paused following disappointing interim results that showed no evidence that convalescent plasma has an overall benefit on patient outcomes in moderately ill people.  Work to search for evidence of benefit in subgroups before organ damage and hospitalisation occurs is now under consideration.

Given the quantity of samples now available, it has been decided that collection of further plasma samples will not be resumed.  The news may seem discouraging, however an important scientific question has been answered.  In terms of the scale and volume of the operation this was a considerable undertaking that has proved that the QUOD infrastructure in close collaboration with the NHSBT’s Blood Service has the capacity and versatility to help and meet such an important demand.

Over 250,000 samples are currently stored in the COVID BioArchive to be used for dedicated research questions and validation of novel tests. Applications are welcome from national and international research groups or health care authorities.

Increasing the Number of Organs Available for Research (INOAR)

Until recently, only organs removed for transplant, but subsequently not transplanted were available to researchers.  Thanks to a collaboration between QUOD and Newcastle University, in partnership with NHS Blood and Transplant, new arrangements have been implemented that will allow hearts, lungs and pancreases which are unsuitable for transplantation to be retrieved for research purposes. This will greatly facilitate ongoing research into developing ways more donated organs can be converted into successful life-saving transplants.

Clare Denison, Lead Specialist – Innovation and Research ODT at NHS Blood and Transplant, said: “This is a significant moment for our organisation and researchers across the country. INOAR will change the face of transplantation and ultimately improve patient outcomes and quality of life in the future.”

This development is particularly exciting for diabetes researchers. Almost 4 million people in the UK are living with diabetes. The condition occurs when the pancreas doesn’t produce enough insulin, or when it can’t produce any at all, which leads to blood glucose levels being too high. Until now, the pancreas has not been removed, or even sampled following the death of people with diabetes during organ donation for transplantation.  Research into the mechanisms preventing normal pancreatic insulin production in diabetes has therefore been limited to the small number of post-mortem samples currently stored in the UK.

Dr Elizabeth Robertson, Director of Research at Diabetes UK, said: “This is an exciting step forward that we hope will rapidly advance our understanding of the causes and progression of diabetes … world-class scientists will now have vital access to pancreatic tissue, propelling our knowledge of diabetes forward and bringing us a step closer to a world where diabetes can do no harm.”

Covid-19 Update: QUOD Resumes

QUOD and NHSBT are delighted to let you know that QUOD sample collection has resumed as of Tuesday 28th July.

Due to the commitment and help from all of the QUOD collaborating partners, the QUOD biobank has been able to facilitate approximately 60 research projects and supported research groups to successfully apply for almost £ 9M of national and international funding, focusing on different aspects of donor organ quality and transplantation. Within the next few weeks we will also reach the milestone of 5,000 organ donors that have been included in the QUOD bioresource.

We are looking forward to getting back to work again and would like to thank all involved in QUOD for their ongoing support!

QUOD Awarded Five-Year Funding Renewal from NHSBT

NHS Blood and Transplant has awarded £2.4 million to the Quality in Organ Donation (QUOD) programme, hosted by the University of Oxford on behalf of the national consortium of transplant centres, to extend the biobank infrastructure until 2025.

QUOD is a unique national biomedical resource combining detailed clinical data from almost all organ donors in the UK with a biobank of blood, urine, and tissue samples taken around the time of donation. This combination of data and samples enables ground-breaking research on biomarkers to predict organ function as well as study mechanisms of organ damage and repair.

Such research contributes to better selection and optimisation of organs for successful transplantation. These efforts are a vital part of NHSBT’s overall strategy to address the lengthy waiting periods for transplant recipients. By enhancing our understanding of which organs are most suitable for transplant, and how organ injury in the transplant process can be prevented and reversed, QUOD aims to increase organ utilisation. This will make more organs available for transplant and reduce the persistent gap between patient need and organ supply.

Since launching in 2013, QUOD has collected over 90,000 samples from almost 5,000 deceased donors. The biobank has received 63 applications, supported by nearly three dozen funders, involving multiple disciplines including proteomics, transcriptomics, immunology, and pathology. Using QUOD resources, investigators have generated dozens of journal articles, dissertations, and major conference presentations, including multiple  Medawar Award nominees at the British Transplant Society congress.

In 2019 the biobank initiated collection of new sample types—cardiac biopsies and bronchoalveolar lavage samples — and the next five years will see the continuation of this collection and the issuing of these samples to new research projects. Plans are underway to add bile and bile duct samples from liver donors. Following crucial support for national initiatives in Normothermic Regional Perfusion and the PITHIA trial, QUOD will continue to offer expertise and logistical help for appropriate clinical trials and service development. Most importantly, the biobank will extend its provision of, and research with whole organs, enabling further development of the whole-organ pathology atlases initiated under a £1.7m MRC grant received in 2017.

Although the introduction of presumed consent for organ donation (i.e, the “opt out” policy) is expected to increase the overall numbers of organs available for transplant, clinicians still need better tools to understand which organs will function best for which donors. Thus QUOD has ambitious aims to facilitate research in transplantation until 2025 and beyond.

Covid-19 QUOD Update

Due to the increasing challenges in the context of COVID-19 in our donor hospitals, NHS Blood & Transplant Organ and Tissue Donation and Transplantation (NHSBT-OTDT) and the QUOD team have decided to pause all QUOD sampling in the UK until further notice.

We hope that this will reduce pressure on the workforce at these difficult times.

Specialist Nurses in Organ Donation and NORS teams are kindly requested to keep new QUOD boxes with an unbroken seal shelved until we are able to resume the sampling for QUOD.

NHSBT and QUOD thank all SN-ODs and NORS team members for their commitment and continued support.

Publications & Presentations: November 2019

QUOD publication printing press

We are very pleased to roll out the first centralised listing of all known publications and presentations based on research using QUOD samples and data! Visit this new website section to peruse details from all 17 presentations and 2 publications (with one more known to be in process for publication).

As we are made aware of more presentations, we will announce via news posts and update the master listing.

Researchers may also be interested in the master list of approved projects and current known statuses.

Did we miss a presentation or publication? Please let us know by emailing quod-research@nds.ox.ac.uk.

5th National QUOD Symposium – 18 November 2019

We would like to invite you to the 2019 Autumn QUOD Symposium to be held in Manchester.

If you are interested in the pursuit of improvement of outcomes after transplantation through translational science, please register and join us for:

  • Consortium Research Presentations
  • Operational Highlights
  • Upcoming Developments
  • Partner Announcements

Time

  • 12pm Arrival and registration
  • 12.15pm Networking and buffet lunch
  • 1pm Symposium starts

Full programme to follow.

Register Here!

SymposiumPoster