Title: Identifying biomarkers and mechanistic pathways to improve organ utilisation and kidney transplant outcomes
Funder: Department of Health and Social Care

Abstract: Research question: Can we identify biomarkers and mechanistic pathways to improve organ utilisation and kidney transplant outcomes? Background: End stage renal failure (ESRF) is a devastating condition that has a significant impact on patient's quality and quantity of life. Kidney transplantation is the optimal form of renal replacement therapy for most patients with ESRF, but organ shortage is a major problem. In an attempt to meet this shortfall, there has been increased utilisation of kidneys from older, more marginal donors. However, these organs have higher rates of delayed graft function and some organs do not provide good kidney function in the longer term. Basic donor demographic data and histological scoring of pre-implantation biopsies have been used to assist clinicians in the decision to use an organ, but these parameters do not provide an accurate prediction of whether a transplant will ultimately have good function. Aims and objectives: We have two overarching aims: Aim 1: To increase the utility of histopathological and demographic data to predict kidney transplant outcome, and to deliver an on-line risk calculator to assist clinical decision-making at the time of transplant. Aim 2: To identify novel biomarkers and mechanistic pathways that predict, or are associated with, kidney graft outcome to improve clinical decision making and reveal novel therapeutic targets.Specific Objectives and Methods: 1. To determine if the predictive value of the histological score generated on a pre-implantation biopsy can be improved by modeling the impact of adjusting the importance assigned to score parameters. 2. To ascertain if the combination of donor characteristics (as per the UK Donor risk index) and biopsy score (the standard Remuzzi score) can better predict outcomes using biostatistics to generate an on-line risk calculator. 3. To determine if bulk transcriptomic analysis (RNA sequencing) of pre-implantation biopsies can be used to identify a gene signature that predicts graft function. 4. To assess whether the use of second harmonics in two-photon microscopy can provide a rapid and accurate assessment of fibrosis in a pre-transplant kidney biopsy. 5. To investigate kidney biopsies using single cell RNA sequencing and mass cytometry to identify immune cell subsets and mechanistic pathways associated with poor graft outcome.Timelines for delivery: The discovery phase of Objective 1 (O1) will be delivered in year 1, the validation by year 3. O2 will be delivered by year 4, and O3-5 during year 5.Anticipated impact and dissemination: This project will generate an open access tool for the transplant community to assist clinical decision-making in organ utilisation. It will also provide mechanistic insights into the pathogenesis of DGF and chronic kidney disease. Ultimately, this will lead to more kidney transplants that last longer, keeping patients off dialysis. We will disseminate our findings via presentations at local and international scientific meetings and in journal publications. We will inform the patients and public of our research in the Cambridge Science Festival and at local NIHR Cambridge BRC open days and evenings.

Lay abstract: Background to the research: Kidney failure is a devastating medical condition. Although we can keep patients alive by offering them dialysis a treatment that cleans the blood their quality and quantity of life is significantly compromised. Perhaps the best way to understand this, is to consider how one of our patients felt about their experience of life on dialysis: Nine hours a week. But it's not just the amount of time that you're on the machine, you know, it's the amount of time you take to get to the hospital and for your machine to be prepared, then you're on the machine, then you go home and then you feel absolutely dreadful, it really is an exhausting experience, you feel nauseous all the time. I couldn't eat much, everything tasted differently to me. And I was sleeping - I was so lethargic, so I literally didn't do anything in between dialysis. As soon as you get off that machine the toxins start to build up again until you get your next dialysis treatment. To me it was just a means of survival. I didn't have any quality of life. Now not everybody feels like thisbut for me it's not something that I wanted to live with for the rest of my life.' (Interview with Allison John, transplant recipient. Radio 4, January 17th 2008 Medical matters). Allison received a living donor kidney transplant from her father, improving her quality of life and survival, but not everyone is quite so lucky. There are currently thousands of patients waiting for a transplant. To try and address this organ shortage, doctors have begun to consider using organs from donors that are older or who have medical problems. Some of these kidneys work well, but some take a long time to get going and have poor function, meaning that the patient ends up back on dialysis.Aims of the research: The aim of our research is to find ways of predicting whether, and to understand why, a kidney is going to work well in the short and long term. This will allow us to develop a tool that can be used by transplant doctors to help them decide whether to use an organ. In the long term, it will also inform the development of treatments that promote kidney transplant longevity. Ultimately, this will lead to more kidney transplants that last longer, keeping patients off dialysis.Design and methods used:We will use mathematical modelling to investigate better ways of using the information we already have about organ donor characteristics, and on the quality of the kidney based on its appearance under the microscope, to produce an on-line risk calculator that can be used by transplant doctors. We will attempt to identify new markers that better predict how well a transplant will work by measuring the expression of genetic information in kidney tissue and using a special microscope that can rapidly identify tissue scarring using samples taken prior to transplant. We will examine the cells in a kidney that can cause inflammation and work out how they contribute to poor graft function. Patient and public involvement: The Cambridge PPI panel and Addenbrooke's Kidney Patients Association will provide important vehicles to ensure that patients and the public are involved at all stages. We will hold workshops with patients on dialysis and those with a transplant to ask them for their ideas about the risks of using organs from marginal donors. We will share our research with patients and the public at the Cambridge science festival and through the NIHR Cambridge Biomedical Research Centre.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.4 SURGERY
Health categories: RENAL AND UROGENITAL