The research projects listed below have been approved by the Steering Committee for access to QUOD samples:
Investigation of transcriptional signatures predictive of suboptimal short- and long-term outcomes in deceased circulatory death kidney transplants
Menna Clatworthy - University of Cambridge
Summary: 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.
Distinguishing between different types of cytomegalovirus infection and their effect on the recipient including long-term kidney function
Paul Griffiths - UCL Medical School
Summary: Transplantation can transmit cytomegalovirus from donor to recipient. The need for immunosuppressive drugs can also make latent virus reappear in the recipient. Transplant centres use antiviral drugs routinely 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.
Investigation of markers of injury and mitochondrial bioenergetics in kidneys from donors with acute kidney injury (AKI)
Catherine Boffa - Nuffield Department of Surgical Sciences, University of Oxford
Summary: 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.
Proteomics of urinary and blood exosomes to identify biomarkers associated with transplantation outcomes
Honglei Huang - Nuffield Department of Surgical Sciences, University of Oxford
Summary: 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.
Pre-donation biomarkers to assess quality of kidney graft of DBD and DCD kidney grafts
Christopher Chalklin - University Hospital of Wales
Summary: 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.
Improving graft function in transplantation with Normothermic Regional Perfusion: A pilot study to investigate the underlying mechanism
Andrew Sutherland - Royal Infirmary of Edinburgh
Summary: 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 effects of NRP on gene expression and microRNA signatures to better understand the therapeutic effect of RNP and how this differs from the standards methods of organ recovery. It will also aim to identify markers that can be used for the evaluation of organs prior to transplantation.
Circulating unmethylated DNA and beta-cell death as a biomarker of graft dysfunction in pancreas transplantation
Iestyn Shapey - University of Manchester
Summary: 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 the transplant recipients afterwards for signs of worsening performance and loss of the transplanted pancreas.
Urinary MicroRNAs as predictors of graft ischaemic injury
Donald Fraser - Institute of Nephrology, Cardiff University
Summary: 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 the 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.
Investigation of injury pathways and mitochondrial bioenergetics in kidneys and livers after brain (DBD) and circulatory death (DCD)
M. Letizia Lo Faro - Nuffield Department of Surgical Sciences, University of Oxford
Summary: 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 survivals, 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.
Molecular signatures of donor kidney quality as predictors of long term outcomes
Maria Kaisar - Nuffield Department of Surgical Sciences, University of Oxford
Summary: Despite the persistent shortage of organ donors, 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 the donor organ quality prior to organ explantation and make informed decisions of which organs should be discarded or transplanted.
We have embarked in 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 development of diagnostic tools of donor organ quality in parallel of expanding our understanding of the underlined mechanisms of kidney ischemia and identify new targets of intervention.
Investigation of the mechanisms of injury and stress response in kidneys from DBD donors - Correlation with delayed graft function (DGF) vs immediate function (IF)
M. Letizia Lo Faro/Maria Kaisar - Nuffield Department of Surgical Sciences, University of Oxford
Summary: Transplantation represents a very successful treatment for end stage organ failure and several 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 (Kaisar et al. submitted). 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.
Proteomic signatures in donor blood as diagnostic tools of donor kidney quality and predictors of 12 month outcomes in kidney transplantation
Maria Kaisar - Nuffield Department of Surgical Sciences, University of Oxford
Summary: Despite the persistent shortage of organ donors, 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 the donor organ quality prior to organ explantation and make informed decisions of 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 predictive of 12-month kidney function in the recipient following transplantation. Our proposed research will lead to the development of clinical tools of 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 ischemia or repair.