Quality and Safety in Organ Donation Tissue Bank - Expansion to include Pancreas/Islets, Heart and Lungs

Organ transplantation saves thousands of lives every year and is the treatment of choice for end stage organ failure. Despite awareness of importance of transplantation, a gulf remains between the supply and need for life-saving organs. This is predicted to worsen over the next decade, making this disparity a key challenge facing the transplant community today. Due to this shortage, nowadays older and higher risk donors are accepted. However, uncertainty as regards transplantability often results in decline and sometimes discard of scarce organs. Between April 2015 and March 2016, 479 patients died waiting for a lifesaving transplant. A further 3,452 patients were temporarily suspended from the waiting list because they were unfit for transplant.
The Quality in Organ Donation (QUOD) Biobank was established in 2012. This unique resource combines collection of detailed clinical information from virtually all organ donors in the UK with blood and urine samples taken around the time of donation and carefully collected small biopsies from a range of organs stored within a central 'bank'. This has been invaluable in research focused on understanding how stress associated with becoming an organ donor around the time of death affects control of important whole body systems such as blood pressure and glucose levels in addition to impact on specific organs. This has already enabled otherwise impossible research focused on better selection and optimisation of organs enhancing successful transplantation.
The pancreas, heart and lungs work in concert to maintain glucose levels, blood pressure and effective oxygenation throughout life. The extreme stress around the time of death has a major impact on these control systems. Despite a huge unmet clinical need, 'conversion' of these organs into successful transplants is much lower than in kidney transplantation. Impairment and failure of these organs is also central to many of the most common and challenging chronic diseases, including diabetes, heart failure; and lung disease.
We propose to expand QUOD to include samples from pancreas, heart and lungs and will work closely with MRC Units to ensure provision to the research community of highest quality state-of-the-art clinical pathology and molecular techniques as well as single cell analysis platforms, in addition to facilities expert in processing organs to retrieve live functioning cells. This will allow us to create detailed atlases and a data library representing the range of normal, acutely stressed and chronically diseased tissues from these organs that can be seldom accessed in life which has severely limited true understanding of mechanisms driving damage and failure. This type of resource linked to such high quality clinical information and a library of new markers associated with these processes and easily monitored from blood samples does not currently exist.
The QUOD remit and proposed expansion will be made accessible to the widest possible scientific and clinical community. It will enable new understanding of causes of organ stress, facilitating new treatments to maximise transplant success and ultimately help to prevent / reverse chronic diseases without need for transplantation. In type 1 and 2 diabetes it is becoming clear that insulin-producing cells are not completely destroyed, offering exciting new possibilities for reactivating function which may ultimately lead to a cure for this burdensome and dangerous disease. Deeper understanding of mechanisms underlying heart pump failure will facilitate increased numbers of heart transplants but also new treatments for all with chronic heart failure targeting specific processes damaging the muscle. Elucidation of the causes of scarring lung disease will be accelerated through this resource. Moreover, previously impossible parallel research exploring pathological interplay between pancreas, heart and lungs with already collected data on liver and kidney will be enabled.

The QUOD Biobank established in 2012 and funded by NHSBT until 2020, provides a unique, rapidly expanding resource comprising rich clinical data of most UK deceased organ donors; banked peri-donation blood and urine samples underpinning an 'omics' biomarker exploration / bioinformatics core; and a central tissue bank, currently including liver, kidney, ureter, and spleen biopsies from 85% of donors.
A special multi-centre HTA site licence comprising 62 hospitals across the UK has been awarded to NHSBT enabling specimen removal during donation for research banking. A robust and sustainable infrastructure has been established. A bespoke 'QUOD box' is used at the donor hospital to contain all samples including blood, urine, and tissue biopsies. Bloods are collected in specific tubes to fulfil individual requirements. Tissue biopsies are preserved in buffered formalin to be processed into formalin fixed paraffin embedded (FFPE) tissue blocks for histological sectioning and analysis. Additional biopsies are collected in RNAlater and snap-frozen for banking to enable metabolic, proteomic and DNA studies.
We propose expansion of sampling protocols to include collection of minimally invasive pancreas, heart and lung tissue biopsies as well as bronchioalveolar lavage samples. In addition, selected untransplanted pancreata, hearts, and lungs representing the breadth of normal, acutely stressed and chronically diseased clinical phenotypes will be transported to processing centres in Newcastle / Oxford for systematic biopsy collection, in depth phenotypic characterisation and structured pathology reporting to create searchable atlases and quantitative analyses linked to clinical data and serum proteomic biomarker library. Blocks for FFPE, frozen sectioning and EM will be stored and available for further analysis including tissue microarray, RNAScope, single cell sequencing. Live cells including intact pancreatic islets will be isolated for functional / single cell analysis.

QUOD currently focuses on kidney and liver research, collecting blood, urine and tissue samples at several time points during donation to identify mechanisms of injury/repair in organ donors affecting outcomes after transplantation. QUOD includes a robust linked integration with data in the UK donor/transplant base, hosted by NHSBT, and one of the best of its kind. Cerebral injury with donation after brain death (DBD) or after circulatory death (DCD) accompanied by warm ischaemia results in complex pathways causing hypoxia and cellular stress followed by extreme systemic changes and a pro-inflammatory and pro-coagulatory state. This increases susceptibility for organ damage, aggravated by organ preservation and transplantation, increasing the chance of graft failure.

With a persistent gap between organ supply and clinical need, centres nowadays accept older and higher risk donor organs. The challenge is to successfully transplant these organs without further compromising outcomes. Exploring mechanisms behind ischaemia/reperfusion injury, identifying biomarkers to predict graft survival, and enhancing donor management are necessary. As mechanisms involved (cellular stress, hypoxia, hypoperfusion, hyperglycaemia) are clinically important and also of interest beyond pure transplant research, the expanded QUOD biobank will help a wider community, supported by applications funded by disease-specific charities. Expansion to all donor organs will significantly increase the research potential, attracting new scientific platforms. Through this application, we will add a national collection to QUOD of pancreas, heart and lung samples currently unavailable to the research community.
Using the existing QUOD infrastructure, pancreatic biopsies will be obtained from up to 500 organs per year retrieved for potential solid organ or islet transplantation and additional tubes added to the QUOD box. Pancreata which are not transplanted (from donors with/without pre-existing / stress-induced hyperglycaemia) will be transported to islet isolation facilities in Oxford and Newcastle for macroscopic assessment, multiple biopsy and islet isolation.

Similarly, cardiac biopsies will be obtained from up to 400 transplanted organs per year, with a similar number taken from non-used hearts. Bronchioloalveolar Lavage samples and tissue biopsies for lungs will be taken from up to 400 lung donors per year, including tissue specimens from those not retrieved for transplant.
The biobank links to the extensive NHSBT data repository for donor and recipient clinical data aligning with the MRC's strategic goal to deliver discoveries from data to improve public health. The translational research resulting from the proposed collection has the potential to reduce healthcare costs as outlined in the MRC's future vision. An increased pool of suitable donor organs can significantly reduce the number of patients relying on intensive care treatment due to organ failure. Intensive study on impact of organ donation on tissue function will facilitate development and optimisation of non-transplant therapeutics potentially transforming outcomes within the healthcare system for chronic diseases currently imposing a huge financial and human burden.

The proposed widened remit of QUOD will provide an invaluable resource for UK academic centres, registered with UKCRC, externally accessible and searchable through integration of the QUOD database with the Achiever Tissue Sample Tracking system established in collaboration with the Newcastle Molecular Pathology Node. Informed by the pathology atlas created from representative slides from each stored tissue block, further serial sections will be provided for research projects and linked to the 'omics' library in Oxford as well as clinical data base hosted by NHSBT. The research outputs will lead to the generation of new hypotheses and targets feeding further translational experimental research, a core goal.