NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigation of the role of regulatory B cells in transplantation.
Funder: Wellcome Trust

Abstract: Transplantation is the most effective treatment for irreversible organ failure. Organ acceptance is currently achieved with powerful immunosuppressive drugs; their action has substantially reduced the risk of early rejection. However, organ survival in the long-term remains a major problem and these immunosuppressive agents have serious side-effects including life-threatening infection and cancer. An ideal solution is to control the immune response only to transplanted tissue, removing the need for immunosuppressants i.e. 'tolerance.' The immune system normally controls unwanted immune responses with cells termed regulatory T cells (Treg). These cells have been successfully isolated at The Transplantation Research Immunology Group (TRIG). A less well understood immune cell recently associated with transplant tolerance, termed regulatory B cell (Breg), has been identified in human kidney transplant recipients (KTRs), at TRIG. This project will study actions of Breg, to underst and their role in transplant tolerance. The study will examine the relationship of Breg and long-term survival of transplanted organs in human KTRs. Mice developed to have a human immune system and then transplanted with human vessel will be used to produce patterns of rejection closely resembling clinical disease. The study will focus on harnessing Breg and Treg activity to induce transplant tolerance in these mice.


Research activity codes: 5.4 SURGERY
Health categories: RENAL AND UROGENITAL
Title: The pathophysiological role of complement regulation in disease.
Funder: Wellcome Trust

Abstract: There is evidence that suggests that in some situations a group of proteins in blood may damage our own tissues. This system of proteins is called the complement system. The complement system is an important mechanism through which the body defends itself against infection. It is also part of the way in which the body generates inflammation. Sometimes the system is activated in the absence of an appropriate trigger (e.g. an infection) and spontaneous inflammation and damage to the bodys tissues occurs. The reason for this is thought to relate to failure to keep the system switched off or to a failure to contain and limit the inflammatory response to sites of injury or infection. We now know that this defect is due to abnormalities in a network of proteins that controls the complement system. These are collectively termed complement regulatory proteins. Examples of human conditions associated with impaired regulation of complement are chronic kidney disease, blindness in elderly individ uals and meningitis. My research aims to understand the mechanisms through which these regulatory proteins fail to work appropriately. I also want to determine ways in which we could develop treatments that would safely restore normal control of the system.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Understanding the origins of pathogenic IgA in IgA nephropathy.
Funder: Wellcome Trust

Abstract: In IgA nephropathy (IgAN), serum and mesangial IgA is enriched for IgA1 molecules that are polymeric, display low antibody affinity and are poorly galactosylated at their hinge region. These features are typical of IgA normally produced at mucosal surfaces and this contrasts with that usually present in the systemic compartment. However, in IgAN, numbers of polymeric IgA1-producing plasma cells are reduced at mucosal sites and increased in systemic sites. This Fellowship will test the hypothesis that in patients withIgAN, polymeric, poorly galactosylated IgA1 is synthesised by a population of mucosally-primed IgA+ B cells which mis-traffic to the systemic circulation. I aim to identify the population of IgA+ B cells which produces poorly galactosylated polymeric IgA1 in patients with IgAN and healthy controls. I will use flow cytometry to isolate IgA+ plasmablasts and will carry out microarray analysis and Q-PRC to establish important cell phenotypes particularly relating to O-glycosyltransferase, J-chain expression and homing characteristics. I will immortalise specific cell populations to allow study


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: The effect of aging upon renal injury and repair
Funder: Wellcome Trust

Abstract: Acute kidney injury (AKI) predominantly affects the elderly and carries heightened risks of death and chronic kidney disease in survivors. No specific treatments exist to promote survival or recovery of kidney function. The explanations of the susceptibility of the elderly to AKI and their impaired ability to repair the kidney remain unclear. Exciting recent work demonstrates that defective repair of other parts of the aging body such as the spinal cord reflects changes in the behaviour of blo ods cells called macrophages. This project will probe the origin of the worsened AKI and impaired recovery seen with aging, examining altered responses of the cells in both the blood and the kidney. I will test the relative importance of these populations using a novel system allowing determination of the effects of both young and old blood cells within the same aged (or young) kidney. On establishing the key cell populations, further experiments will dissect the mechanisms impairing kidn ey repair. This information will enhance our understanding of kidney repair, instruct the development of novel AKI therapies and be of potential impact in diseases such as heart attack and stroke.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Wellcome Trust-Beit Prize 2012/2013 Drug-associated acute kidney injury: who gets it, when and why?.
Funder: Wellcome Trust

Abstract: Acute kidney injury (AKI) is associated with mortality, prolonged hospital stay and accelerated kidney disease. It appears to be increasing but the true incidence of AKI and whether it is changing remains unclear. Some evidence suggests AKI can be caused by commonly prescribed medications, often during acute illnesses. Drug-associated AKI may be avoidable but at present it is unclear who is at risk, when, and the role of co-prescriptions and acute illnesses. Full understanding would allow develo pment of prevention strategies and accurate prescribing guidance. Following validation of case definitions, this research will use cohort and self-controlled case series in three large electronic-health databases to meet the following goals in a UK community setting: 1. To determine the relationship between AKI defined by biochemical parameters and by administrative coding, to obtain detailed estimates of the incidence of drug-associated AKI, and to understand whether there is a true increase over time. 2. To determine the mortality, need for hospitalisation and dialysis following drug-associated AKI 3. To determine which chronic comorbidities are associated with increased risk of drug-associated AKI 4. To determine whether the risk of drug-associated AKI is raised following acute infections, and if so which infections are associated with increased risk.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: RENAL AND UROGENITAL
Title: Drug-associated acute kidney injury: who gets it, when and why?.
Funder: Wellcome Trust

Abstract: A sudden decrease in kidney function or acute kidney injury (AKI) is common and associated with an increased risk of death, prolonged hospital stay and risk of permanent kidney failure. Rates of AKI are increasing and causing significant cost to the NHS. Some limited evidence suggests that AKI can occur as a side effect of ACE inhibitors (ACEI) and angiotensin-receptor blockers (ARBs), particularly when prescribed with water tablets (diuretics) and anti-inflammatory pain killers. ACEI and ARBs a re commonly prescribed for conditions such as high blood pressure and heart problems At present it is not known how common AKI is among people taking these drugs, whether there are any conditions (e.g. diabetes, existing kidney problems) that modify the risk and the role of acute infections such as gastroenteritis. This is important because if it was understood who is likely to develop AKI and in what circumstances, strategies could be developed to prevent AKI. This research proposal aims to us e very large numbers of linked electronic health records to answer these important questions with the aim of substantial savings to the NHS and to prevent serious illness and death.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: RENAL AND UROGENITAL
Title: Long term outcomes of acute kidney injury - Establishing prognosis to design optimal management.
Funder: Wellcome Trust

Abstract: Acute Kidney Injury is a common problem that occurs in up to 1 in 5 patients admitted to hospital with acute illness. Sometimes it is the single reason to be admitted but usually it is associated with many different serious illnesses. It leads to the rapid loss of kidney function with some patients needing dialysis treatment. Unfortunately some individuals do not survive and those who do recover may in the future develop problems with their health. There is a lack of knowledge and understandin g of how we can identify and treat people who are less likely to do well. This project will address this significant information gap. Historic data for a large group of patients (70,000) who have previously had blood tests will be analysed and those who have suffered Acute Kidney Injury will be identified. This finding will then be linked with other important health care information to investigate which patients do develop long-term health problems and how are they best identified at the time of their initial illness. We hope that these findings will provide valuable information for patients and their doctors, helping us all design a better health service.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: RENAL AND UROGENITAL
Title: Defining the bi-directional relationship between cancer and kidney disease
Funder: Chief Scientist Office, Scotland

Abstract: Cancer and cardiovascular disease are the two commonest causes of morbidity and mortality worldwide. Approximately 5-10% of population have chronic kidney disease (CKD). Both cancer and cardiovascular disease are present in excess in patients with CKD, and associated with significant morbidity and early mortality. With an ageing population, the burden of CKD, cancer and cardiovascular disease is ever increasing. Onco-nephrology, the study of the interface between oncology and nephrology, aims to understand the interplay between cancer and kidney disease. CKD is associated with increased incidence and possibly worse outcome from cancer. Cancer treatments, especially newer systemic anti-cancer treatments, are associated with nephro- and cardio-toxic side effects, presenting clinically as acute kidney injury, hypertension, proteinuria or exacerbating existing CKD. We will address a number of important issues where kidney disease, cancer and cardiovascular disease either co-exist or are mutually exacerbated using large, readily available datasets and data linkage from general population, cancer and CKD cohorts in Scotland and the UK. We anticipate that this will increase understanding of the interplay between cancer and CKD, and will lead to improvements in care for patients with co-existent cancer and kidney disease


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: RENAL AND UROGENITAL;CANCER AND NEOPLASMS;CARDIOVASCULAR
Title: Noon-invasively quatifying, understanding and reverssing myocardial fibrosis in renal failure
Funder: Chief Scientist Office, Scotland

Abstract: Patients with kidney failure commonly die from heart disease. Part of the reason for this is because the heart muscle of people with kidney disease becomes unhealthy and fibrosed (stiff). Reversing this heart abnormality may make people with kidney disease live longer and healthier lives. However, not all patients develop fibrosis to the same extent. We would like to reliably identify how much fibrosis a person’s heart muscle has so we can try and treat it. Currently, the only way to do this for certain is to take a heart biopsy (sample). This technique is not suitable for everyone and carries significant risks. We propose to use a non-invasive technique with MRI scanning of the heart called T1 mapping to measure exactly how much fibrosis there is. We have already shown that T1 mapping values are high in haemodialysis patients. We think this is because of fibrosis. However, we need to make certain that it is not because of excess water that kidney patients might be carrying. We hope to confirm this in a small group of haemodialysis patients by asking them to first have an MRI scan with T1 mapping and a CT scan to look at heart vessels before dialysis and another MRI after dialysis. To identify a treatment for fibrosis, we want to perform T1 mapping on mice with kidney failure. We can then extract mice heart tissue and measure exactly the amount of fibrosis present and compare the amount of fibrosis with T1 mapping values. We will use the mice heart tissue to try and better understand what causes the fibrosis to happen. We then want to give mice treatments to potentially reverse the fibrosis and improve heart function. If successful, in the future we would like to implement similar treatment for kidney patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL;CARDIOVASCULAR
Title: Predicting Cardiovascular disease risk in ckronic kidney disease
Funder: Kidney Research UK

Abstract: Cardiovascular (CV) disease risk in chronic kidney disease (CKD) remains poorly described beyond simple risk stratification by CKD stage. General population CV risk tools either do not account for CKD (for example the Framingham risk tool) or use a crude, universal adjustment for all CKD (such as in QRisk2) regardless of the staging and thus difference in CV risk. The PSP-CKD study was a cluster randomised controlled trial in primary care study in relation to CKD. The trial commenced in 2010 and recruited 49 General Practices who contributed a total of 30,000 patients with CKD and a total of 3 years of follow-up. The aims of this project are to refresh the PSP-CKD database to include 5 years of follow-up, to externally validate existing risk scores using the PSP-CKD data, to further refine existing risk scores and lfinally, to externally validate, with an independent CKD cohort, any newly developed score. The results of this work will be communicated to appropriate stakeholders, such as Kidney Research UK and Clinical Commissioning Groups, and published in a high impact peer-reviewed journal.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: RENAL AND UROGENITAL;CARDIOVASCULAR
Title: Pre-clinical assessment of small diameter conduit made from nanocomposite polymer for coronary artery bypass graft application
Funder: Wellcome Trust

Abstract: Current synthetic grafts are largely based on polytetraluoroethane (PTFE) or Dacron perform adequately as large calibre grafts, but are not suitable for coronary artery bypass grafts (CABG) due to the small diameter of the coronary arteries, the low blood flow rates and high occlusion rates resulting in thrombosis and intimal hyperplasia. There is a clinical need for a smaller diameter CABG (<5mm) that mimics the properties of native human artery, and this is being developed by Professor Alexander Seifalian and colleagues at University College London. The conduits are to be made from a novel patented polymer based on polyhexal oligomeric silsequioxanes and poly(carbonate urea) urethane. The translational funding will be used to validate the small diameter cardiac bypass graft in an animal model, experiments that are required in accordance with the regulatory authority requirements for an implantable device.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: RENAL AND UROGENITAL;CARDIOVASCULAR
Title: Salt, Diet & Hypertension: An integrative in vivo physiological investigation of WNK pathway controlled renal electrolyte and blood pressure homeostasis.
Funder: Wellcome Trust

Abstract: This project is designed to directly address a technique/technology gap that has prevented us from answering key biomedical questions in WNK controlled cardio-renal physiology. By modular combination of existing techniques/technologies the project puts forth a novel strategy to address the lack of direct, tubular segment-specific measurements of the renal physiology in vivo that may be integrated with other primary data. By the end of the project several outstanding biomedical questions in field of WNK biology and electrolyte homeostasis will have been directly addressed for the first time, and the first integrated map of distal convoluted tubular functional will have been produced. Key goals: 1) Develop an in vivo technique to simultaneously quantify renal tubule ion transport and intracellular chloride and pH by combining live imaging of GFP-based biosensor transgenic mice and micropuncture/perfusion techniques. 2) Integrate tubular ion transport functional readouts with bio chemical and morphological data obtained from microdissected tubule segments and whole tissue 3D fluorescent imaging using the CLARITY technique. 3) Validate the current model (Figure 2) used to explain the relationship between blood potassium levels, intracellular chloride, WNK/SPAK/NCC activity and blood pressure; reconcile the model with the paradoxes presented by Gordon and Gitelman syndrome.

Lay abstract: This project is designed to address a technique/technology gap that has prevented us from answering questions about how our kidneys function and control blood pressure. By combining existing techniques/technologies in an innovative way I will be able to directly look at how the different parts of the kidneys work in living animals and take multiple measurements which I can combine together for the first time. By the end of the project several outstanding biomedical questions in kidney function a nd blood pressure control will have been directly addressed in live animals for the first time, along with detailed maps of specific kidney section functions produced. Key Goals: 1) Develop a technique using genetically altered mice that can emit different colour light to report the acidity and chloride levels inside their cells, as well as using microscopic glass needles to collect and measure the fluid salt content from different kidney parts. 2) Combine information from (1) with meas urements of various proteins levels from each kidney section and 3D images of the kidney structures 3) Validate if our current understanding of how salt (sodium and potassium) affects blood pressure is correct in health and rare diseases.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: RENAL AND UROGENITAL;CARDIOVASCULAR
Title: Investigating the interplay between interleukin-11 (IL-11) and senescence in cardio-renal aging.
Funder: Wellcome Trust

Abstract: As chronological age increases, even in the absence of disease, vital organs accumulate changes which cause them to function less efficiently. Impaired efficiency of organs such as the heart or kidney are particularly common in older people causing the development of symptoms and require medical attention or hospital admissions. Cells accumulate damage to their DNA with age which causes these cells to enter a protective dormant state known as senescence. This prevents these cells from dividing and passing on the damaged DNA, however, senescent cells release molecules which cause neighbouring cells to produce scar tissue called fibrosis which impairs the efficiency of these organs. Interleukin-11 is one of these molecules which is known to cause fibrosis in multiple different diseases and blocking its effects reduces the amount of fibrosis. We plan to use treatments to block Interleukin-11 in ageing mice to identify the effect this has on the health of these mice and the amount of fibrotic tissue that they develop. We will also analyse the effects of senescent cells on the surrounding tissues to identify the benefit of treatments which specifically remove these cells or stop their contribution to scar formation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL;CARDIOVASCULAR
Title: The Social Dynamics of Female Genital Mutilation/ Cutting (FGM/C)
Funder: The British Academy

Abstract: One key but unmet target for global policymakers is to end female genital mutilation/cutting (FGM/C). Over twenty-five million, two thirds of Ethiopian women are thought to be cut, the second highest national number in Africa. Establishing how and why FGM/C persists in high-risk communities has proven difficult as being an illegal practice people may be inclined to misreport their views and experiences. Further, little is known of how FGM/C norms are socially transmitted between individuals and communities. By combining ethnographic, social network analyses and novel survey techniques, we address the need for more accurate data on FGM/C beliefs and attitudes, and the transmission of social norms which underpin its acceptability among people in rural Ethiopia. This work will reveal how FGM/C is socially maintained, thus potentially how it can be eliminated e.g. by identifying the key opinion leaders who could be targeted for anti-FGM/C campaigns in this and similar communities.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;7.1 INDIVIDUAL CARE NEEDS
Health categories: RENAL AND UROGENITAL;DISPUTED AETIOLOGY AND OTHER