NIHRDataInsights/HRCSData huggingface dataset:
Title: Adiposity and kidney disease: observations from large blood-based prospective cohorts across a wide range of different populations
Funder: Medical Research Council

Abstract: 1. TO DERIVE RELIABLE OUTCOMES (RENAL AND NON-RENAL) FOR THE MEXICO CITY PROSPECTIVE STUDY AND CKD/ACUTE KIDNEY INJURY (AKI) OUTCOMES FOR 2 OTHER LARGE BLOOD-BASED PROSPECTIVE COHORTS (UK BIOBANK [UKB] & CHINA-KADOORIE BIOBANK [CKB]) For the Mexico City Prospective Study, fieldwork is necessary to confirm successful linkage of participants to hospitalisation records, and verify clinical diagnoses. For CKB, a traditional hospital notes based adjudication process will be undertaken in about 5000 recorded outcomes, including hospitals admissions recorded as CKD, 'acute renal failure', 'unspecified renal failure'. In UKB, data from secondary and primary care will be combined to identify CKD stages and hospitalisation for AKI and these algorithms tested using the baseline measured kidney function. 2. TO ASSESS ASSOCIATIONS BETWEEN MEASURES OF GENERAL/CENTRAL ADIPOSITY AND RISK OF CKD AND ACUTE KIDNEY INJURY ACROSS DIFFERENT POPULATIONS To quantify the magnitude of associations between measures of general/central adiposity and risk of CKD/AKI across different populations using data from 3 blood-based cohorts (CKB, UKB, and the Mexico City Prospective Study) which have complete baseline adiposity measurements and a large number of prospectively collected outcomes. 3. TO EXPLORE MECHANISMS FOR THE ASSOCIATION BETWEEN INCREASED ADIPOSTY AND CKD RISK, INCLUDING MENDELIAN RANDOMIZATION EXPERIMENTS Diabetes is a mechanism by which adiposity may cause kidney diseases, but increasing BMI is a CKD risk factor in people without diabetes. To investigate what is causing this association, genotyping data from SHARP, CKB, UKB and eventually the Mexico City Prospective Study will assess whether adiposity is likely to be a cause of non-diabetic kidney disease or not. Whether genetically elevated blood pressure is a mediator of CKD progression or incident CKD will then be assessed. Genotyping/biomarker data will then be used to explore new hypotheses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Characterisation of glycan ligands recognised by collectin-11 in ischaemic kidney and development of a specific antagonistic probe
Funder: Medical Research Council

Abstract: Pattern recognition of carbohydrate changes on injured tissue is of medical importance, since it may trigger inflammation and cell death. We have partially characterised the features of carbohydrate structures on hypoxic renal tissue that are bound by the pattern recognition molecule collectin-11 (CL-11) and which trigger complement activation and acute kidney injury. We have established that the major glycans in the kidney detected by CL-11 are fucosylated and furthermore have identified subsets of fucosylated ligands that bind CL-11, including blood group related sequences of the ABH system. These observations suggest a blood group related structure or structures containing alpha1-2 linked fucose are likely to be major ligands for CL-11 and imply there may be multiple fucosylated CL-11 ligands on stressed cells. To test this hypothesis, we propose to identify the main glycan structures recognised by CL-11 in ischaemic renal tissue and determine the range and type of proteins that function as carrier molecules in cells. We will make use of a tissue-derived glycan array to screen for CL-11 binding ability and elucidate the structures of strong binding ligands by micro-sequencing. We will validate their biomedical relevance by determining their presence in human biopsy tissue. We will design of a novel CL-11 analogue that has potential application as a probe to detect and block the recognition of these damage-associated carbohydrate ligands. Our objective is to clarify the biochemical and structural changes caused by hypoxia and explain how they lead to lectin pathway engagement and inflammation, and develop tools that could subsequently be adapted for clinical exploitation as imaging or therapeutic agents. The work has implications for acute ischaemic kidney injury and transplantation in the first instance.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: MICA: NURTuRE - changing the landscape of renal medicine to foster a unified approach to stratified medicine
Funder: Medical Research Council

Abstract: Renal disease is often complex and chronic with variable phases of activity, resulting in advances in therapies being slow and difficult to introduce systematically. We have realised a sustainable national infrastructure, NURTuRE (National Unified Renal Translational Research Enterprise, nurturebiobank.org), kick-start funded by an industry/academic consortium partnership (£2.05M) to systematically permit recruitment of any patient with kidney disease to participate in research lifelong. Crucially, this includes meticulous biosample collection from every patient, protocolled to stringent industry standards. NURTuRE establishes a national network of research nurses to recruit patients into two pilot cohorts of kidney disease (1) a rare disease, idiopathic nephrotic syndrome (INS) and (2) a common condition, chronic kidney disease (CKD), held within an established registry. We are recruiting 1000 INS and 3000 CKD patients over 2 years (2017-19). This proposal will assemble a unique dataset from those cohorts, combining analysed biomarkers with detailed temporal clinical and routine biochemical data. By the end of the funding period the aim is to achieve a paradigm shift in mechanism-based stratification for INS, and additionally establish proof of principle that this resource can yield rich datasets for discovery of stratification paradigms in CKD. The platform is based on solid momentum over the last 7 years, of having established in the UK firstly a renal rare disease registry (RaDaR) based on substantial core infrastructure, under the governance of the UK Renal Association, with a Rare Disease Committee, and RaDaR operational management board. Additionally the IT is based within the established UK Renal Registry, and linked to Renal Patient View, both NHS embedded organisations. The proposal aims to achieve the first re-classification of INS in decades, as well as advancing mechanism based endotypes of CKD which can be built upon in future studies


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL
Title: Pre-Clinical Evaluation of a Myoblast Delivery Product for Muscle Regeneration
Funder: Medical Research Council

Abstract: Incontinence is a significant unmet clinical need for which cell therapy offers an innovative medicine to restore sphincter muscle function. Clinical studies to date using autologous muscle progenitor cells (myoblasts) have been disappointing, probably due to suboptimal manufacture and clinical delivery of the product. Conventional manufacture of autologous myoblasts involves cell isolation from biopsies and culture on substrates not suitable for implantation into the body. The adherent cells require detachment during passaging and prior to clinical transplantation, delivering to the patient a sub-optimal product, i.e. adherent cells in a suspension, which may quickly become non-viable or migrate from the implant site. We propose expansion and delivery of myoblasts attached to biodegradable, clinically approved microparticles. The provision of a temporary degradable substrate will increase the potency of the delivered cells and help retain them at the target site. This project intends to demonstrate the benefit of delivering myoblasts attached to the surface of TIPS microparticles via greater persistence, retention and engraftment of transplanted cells at the target site compared with cells delivered conventionally in a cell suspension. The quantity of cells delivered will be equivalent to the number used in clinical trials for faecal incontinence. Phenotypic stability and engraftment of the transplanted cells will be investigated, along with an assessment of local tolerance of the microparticles including inflammation, scarring and bioabsorption at the site of implantation over pre-determined time intervals. If successful, the project will provide unequivocal evidence that delivery of cells anchored to biodegradable microparticles results in greater persistence and retention of viable cells at the implant site and will de-risk subsequent more extensive pre-clinical evaluation of the technology that will be required before clinical testing can begin.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: RENAL AND UROGENITAL
Title: IMPC - Exploration of the potential of C7 blockade as a target for immune therapy in complement mediated kidney disease
Funder: Medical Research Council

Abstract: C3 is the central protein of the complement proteolytic cascade. We have generated a sophisticated floxed knock in mouse which carries a single-point mutation, p.Asp1115Asn (Met1) in C3 (C3-D1115N); this gain-of-function change in man results aHUS. Homozygous C3-D1115N mice develop severe kidney disease by P21 with all the hallmarks of a thrombotic microangiopathy disease mediated by over active complement, i.e. aHUS. We have shown that use of a monoclonal antibody to C5 in the C3-D1115N reverses the disease in the mice, in a manner analogous to eculizumab in man. We now wish to establish if the role of membrane attack complex is the critical factor in the development of aHUS and test whether targeting C7 will be sufficient to block disease. To achieve this, we will: 1. Establish if disease is present in homozygous C3-D1115N mice after backcross onto C7-/- deficient animals; using histological and biochemical analysis. 2. Use the C7 deficient mice to develop highly specific antibodies that will ideally block the function of both human and mouse C7; tested in both classical and alternative pathway based haemolytic assays. This study will pave the way to potential new drugs for the treatment of complement mediated diseases. It will give concrete data on whether an intact membrane attack complex is necessary and sufficient to precipitate aHUS. These studies will be of immediate interest to industry and the ongoing efforts to generate drugs to replace eculizumab.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Piezo1 as a novel mediator in the pathogenesis of polycystic kidney disease
Funder: Medical Research Council

Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the commonest inherited cause of kidney failure, caused by mutations affecting polycystin-1 (PC1, PKD1) and polycystin-2 (PC2, PKD2, TRPP2). Treatment for this condition is currently very limited. The mechanisms leading from mutation to disease phenotype remain unclear, but involve cell proliferation in the cyst wall under conditions of mechanical stretch. Piezo1 is a mechanosensitive membrane protein, which physically interacts with and is negatively regulated by PKD2, and has been implicated in stretch-induced proliferation. This project aims to understand the partnership between PKD2 and Piezo1, by testing the hypothesis that genetic disruption of PKD2 causes polycystic kidney disease through failure to appropriately suppress Piezo1, leading to increased stretch-induced proliferation in cystic epithelium. I will do this by generating molecular models of PKD2 and Piezo1 channels, to study the physical interaction between these channels in model membranes. The output of these models will be validated and refined in a 2-way process, using cellular models to test the effect of targeted PKD2 mutation on the ability to interact with Piezo1, and Piezo1 function. These effects will be measured using patch clamping, co-immunoprecipitation, and fluorescence lifetime imaging microscopy. This project will give new insight into the function of PKD2, and determine the role of its interaction with Piezo1 in the pathogenesis of ADPKD. Improving understanding of this disease, and potentially uncovering a new pathway in its development, will bring us closer to expanding the limited treatment options for this severe disease. More immediately, the results of this research will advance knowledge in the fields of kidney research, mechanosensation, and channel physiology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Regulatory T cells in Highly Sensitised Renal Patients to Improve Outcomes after HLA-Antibody Incompatible Transplantation.
Funder: Medical Research Council

Abstract: Highly immunologically sensitized patients account for 1/3rd of the renal transplant waiting list and have circulating antibodies (Ab) against a broad array of different HLA. Getting a suitable donor kidney for them is difficult, because of the risk of immediate Ab-mediated rejection (AMR), so they wait a long time. At Guy's, highly sensitized patients can undergo Ab-removal prior to transplantation, as a way of avoiding the risk of immediate AMR. This option has no detrimental impact on patient survival compared to waiting on dialysis. But these patients suffer higher rates of rejection and shortened graft lives, consequent on activation of immune memory responses. Guy's is also a pioneer of regulatory T cells (Treg) therapy in the UK, and my project is to investigate whether these highly specialized cells can be used in sensitized patients to suppress memory responses. Building on established techniques, I will first document the number and phenotype of Treg subsets, and determine whether, using ELISPOT assays for anti-HLA interferon gamma production, patients have any evidence of endogenous suppression of HLA responses. Second, I will expand Tregs from patients in vitro and ask whether by titrating increased numbers into the ELISPOT, I can suppress specific responses to HLA molecules. As part of this objective, I will define if specific maneuvers to enhance interactions with antigen presenting cells, such as transducing with chimeric antigen receptors, can improve Treg suppressive ability. This work will inform a "second generation" of Treg therapy. Finally, I will take samples from patients enrolled in a clinical trial of first-generation Tregs, and document the impact on responses to clinically relevant HLA; the aim is to show that the ELISPOT assay can be used to document the efficacy of administered Tregs, which will have a direct impact on whether the trial is extended into a therapeutic trial in sensitised patients about to undergo transplantation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.2 CELLULAR AND GENE THERAPIES
Health categories: RENAL AND UROGENITAL
Title: MicroRNAs Predict and Regulate Heme Oxygenase-1 Expression
Funder: Medical Research Council

Abstract: Background: We have identified a novel PBMC microRNA signature which is strongly associated with high heme oxygenase -1 (HO-1) response to heme arginate (HA) treatment. Aims: To assess the role of miRs as both predictive biomarkers and regulators of HO-1 upregulation following HA treatment, in monocytes and macrophages. Methods HOT2 is a multicentre trial powered to determine if HA improves primary function following renal transplant. A local subset of patients will be recruited to HOT2R (HOT2-Research) to investigate: 1) the stability and validity of miRs in predicting HO-1 response (protein and mRNA) to HA 2) the impact of HA treatment on monocyte phenotype 3) the effect of HO-1 response on clinical outcomes. MiR expression in two completed RCTs employing HA in surgery (HACS, Cardiac and HOLS; Liver) will be performed to determine the generalisability. Concordance between PBMC and serum miR expression will be determined and further correlated with end organ (renal and liver) HO-1 expression in HOT2R and HOLS samples respectively. To mechanistically interrogate factors associated with HO-1 response, we will first use flow cytometry/cell sorting, to examine the cell surface characteristics and miR profile of isolated monocytes in HA treated patients. Using an in vitro model of human monocyte derived macrophages (MDM), the regulation of HA response by miRs will be probed. Anti-miRs and lenti-viruses will be used block and overexpress miRs prior to HA treatment and the effect on MDM HO-1 measured. The impact of miR and HO-1 expression on monocyte and macrophage phenotype will be determined. The transcriptional regulation of these miRs will be explored in vitro and results correlated with trial samples. Outcomes: The potential benefits are twofold: as biomarkers to predict HO-1 response, thereby allowing a stratified treatment approach; and enhancing the understanding of the molecular regulation of HO-1, potentially identifying novel therapeutic targets.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL
Title: Does oral sodium bicarbonate therapy improve function and quality of life in older patients with chronic kidney disease and low-grade acidosis? A multicentre randomized placebo controlled trial
Funder: Chief Scientist Office, Scotland

Abstract: BiCARB is a multi-centre, double blind, placebo controlled, randomised trial evaluating the clinical and cost-effectiveness of oral sodium bicarbonate in the management of 380 older people with chronic kidney disease stages 4 and 5 who have a mild degree of metabolic acidosis. The trial will recruit patients from renal, medicine for the elderly and primary care services across a minimum of 6 UK centres. Male and female patients aged 65 and over with estimated glomerular filtration rate (GFR) of <30 ml/min, not on dialysis, and with serum bicarbonate levels <22 mmol/L will be eligible for participation. Participants will receive a total of 24 months of either bicarbonate or placebo, with outcomes measured at 0,3,6,12 and 24 months. In two of the centers (Dundee & Aberdeen) an optional additional sub-study measuring arterial stiffness and markers of bone health will be assessed in up to 150 of the patients at baseline, 12 and 24 months. Outcomes will include physical function, quality of life, renal function, markers of bone and vascular health, muscle mass, plus a health economic evaluation.

Lay abstract: Many people with advanced kidney disease have high levels of acid in the blood. Acid in the blood is associated with tiredness, muscle weakness, worsening kidney function, problems with bone health (osteoporosis) and blood vessel health. Older people most commonly have problems with kidney disease, but are also most prone to problems with heart attacks, strokes and osteoporosis. Bicarbonate (used in baking powder) is often used to treat high acid levels, but it is not known whether this can improve tiredness, weakness, bone or blood vessel health. On the downside, bicarbonate can raise blood pressure and cause stomach discomfort and bloating. We will conduct a randomised controlled trial to test whether bicarbonate treatment makes older people with advanced kidney disease healthier. 380 patients will receive either bicarbonate or dummy (placebo) tablets three times a day for 2 years. We will test muscle strength and bulk, walking and balance ability, quality of life, kidney, bone and blood vessel function at intervals over the two year period. We will record blood pressure and side effects, record falls, admissions to hospital and contact with GPs, and also test the cost of treatment against the cost of not treating. The results will allow us to tell if the health benefits of taking bicarbonate outweigh the side-effects and problems that it might cause.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL
Title: Resuscitating and reconditioning kidneys ex vivo
Funder: Department of Health and Social Care

Abstract: Use normothermic ex vivo kidney perfusion to assess and sustain deceased donor kidney function and to test novel interventions that might prevent tissue injury and recondition DCD and extended criteria donor kidneys. Ex vivo warm perfusion of human kidneys will be undertaken with a plasma free red-cell based solution at a mean temperature of around 34.6°C for approximately 60 minutes In addition to the interventional studies already outlined above to be performed in discarded human kidneys (mitochondrial biology studies and studies using nanoparticles targeted to vascular endothelium), one of the objectives in this theme is to undertake an early phase 2 study of ex vivo perfusion of DCD donor kidneys (n=30 donor pairs) in years 1-2 to determine the safety and efficacy of ex vivo warm perfusion and to provide baseline data for subsequent pharmacological and biological interventions Evaluate the impact of ex vivo warm perfusion shortly before implantation versus ex vivo perfusion at an earlier time-point (years 2-3


Research activity codes: 6.4 SURGERY
Health categories: RENAL AND UROGENITAL
Title: Point-of-Care Creatinine test before contrast-enhanced imaging
Funder: Department of Health and Social Care

Abstract: The purpose of this assessment is to assess the clinical and cost-effectiveness of point-of-care creatinine tests to assess kidney function, for people who need contrast-enhanced computed tomography (CT) imaging in a non-emergency situation and who do not have a recent serum creatinine measurement.

Lay abstract: Before hospital CT scans are performed, a contrast agent is usually needed to improve image quality. The improved images help clinicians when making decisions about diagnoses or future treatment decisions, across a range of diseases and illnesses. When contrast agents are given intravenously they may occasionally damage the kidneys, particularly in patients whose kidneys already do not work well. A creatinine blood test is therefore used to identify these patients (as their creatinine levels are usually high) so that steps can be taken to minimise or remove the risk of kidney injury resulting from contrast agents. Before a contrast-enhanced CT scan takes place some patients already have a recent creatinine blood test result available, as a result of other medical investigations. Their blood samples will have been analysed in a central laboratory but this process usually takes at least an hour. Other patients do not have a recent creatinine measurement which means their CT scan may be delayed or rescheduled. Sometimes, to avoid risking kidney injury, patients may have scans without having received a contrast agent, though this produces less accurate images. “Point-of-care” devices (handheld, table-top or portable) can rapidly measure creatinine, usually from finger-prick samples, to identify patients at high risk of kidney injury. However, their results may not be as accurate as those derived from laboratories so it is unclear whether or not these devices are beneficial. The purpose of this project is to assess the benefits, harms and the cost-effectiveness of point-of-care creatinine tests used immediately prior to non-emergency, contrast-enhanced CT scans. We will identify relevant studies and analyse the data to see whether the more widespread use of point-of-care creatinine tests can be considered a cost-effective use of NHS resources.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL
Title: Domiciliary REcovery After Medicalisation Pathway (DREAM Path)
Funder: The Urology Foundation

Abstract: DREAM Path is a prospective observational study to assess patient acceptability of remote monitoring devices at home after major pelvic surgery, and to explore the utility of remote monitoring in patients who are at high risk for re-admission.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: RENAL AND UROGENITAL