NIHRDataInsights/HRCSData huggingface dataset:
Title: Advance care planning with older patients who have end-stage kidney disease: feasibility of a deferred entry randomised controlled trial incorporating a mixed methods process evaluation
Funder: Dunhill Medical Trust

Abstract: Background: End-stage kidney disease (ESKD) increases the risks of other major illnesses and sudden death. Advance care planning (ACP) may lead to care more in keeping with patients’ wishes and so reduce distress for patients and families. However, we still need to find out more about the impact of ACP; and also about the best ways to put it into practice. This study is designed to test the research methods for a larger study that would answer those questions. Aim: To determine the feasibility of conducting a deferred entry RCT, alongside a mixed methods study, to evaluate ACP with older patients who have ESKD. Methods: 40 patient/carer dyads will be randomised in a 12 week RCT to immediate or deferred entry groups to allow between group comparisons, before the deferred entry group proceeds to ACP. Intervention processes will be investigated using qualitative methods to identify key factors for implementation success.


Research activity codes: 7.2 END OF LIFE CARE
Health categories: RENAL AND UROGENITAL
Title: Does the phenotype of antigen specific anti-donor memory B cells determine the long-term outcome after renal transplantation?
Funder: Kidney Research UK

Abstract: Objective 1: Phenotype of antigen-binding B cells in HLA-sensitised patients: On PBMC from selected patients on the highly sensitised programme at Guy's (and a small number of healthy controls), HLA-binding B cells will be defined by multicolour flow cytometric analysis using biotinylated HLA proteins (corresponding to mismatched antigens against which the recipient has an antibody). To define the role of B cells in IFNgamma production responses to donor antigens (from living donors) and the same purified HLA proteins will be tested using an ELISPOT assay. In all analyses, responses to CMV gpB protein will act as a control for antigen binding, processing and presentation. Soluble inhibitors of B cell receptor activation and anti-HLA class II blocking antibodies will confirm antigen presentation by B cells. Cross-sectional and prospective analyses will allow detailed correlation between results and functional outcomes and study of the evolution of B cell memory responses. Objective 2: Antigen-binding B cell phenotypes pre- and post-rituximab. ELISPOT patterns and the phenotype of memory B cells (pre- and post- rituximab) will be defined using PBMC from two multicentre RCT's assessing rituximab as induction therapy (REMIND) or as treatment for CR (RituxiCAN-C4). The phenotype of reconstituting HLA-binding B cells will be tested using samples 12 or 24 months post-depletion. Objective 3: Mechanisms of B cell modulation of IFNgamma production by T cells. RNA profiles from HLA-antigen binding B cells with contrasting immunoregulatory properties will be compared, using Illumina's HT 12v4 beadchip arrays. Differentially expressed genes will be identified by ANOVA analyses using Partek's Genomics suit software and validated by quantitative RT-PCR protein expression. In addition, detailed surface phenotyping of described B cell markers will be performed.


Research activity codes: 6.4 SURGERY
Health categories: RENAL AND UROGENITAL
Title: NURTuRE: National Unified Renal Translational Research Enterprise - HBRC Univ of Birmingham
Funder: Kidney Research UK

Abstract: NURTuRE: National Unified Renal Translational Research Enterprise - University of Birmingham

Lay abstract: The UK Renal Research Strategy recognised the need for a kidney biobank. Kidney Research UK has led the collaboration with industry and academia to launch NURTuRE (the National Unified Renal Translational Research Enterprise) - the first kidney biobank covering England, Scotland and Wales and a key resource for the renal research community. The biorepository is collecting and storing biological samples from 3,000 patients with chronic kidney disease (CKD) and at least 800 patients with idiopathic nephrotic syndrome (INS). It will provide a resource for fundamental and translational research. In addition to the samples of plasma, serum, urine, DNA and tissue that are stored, the repository has the considerable advantage of containing associated linked clinical data, through the UK Renal Registry. Running over a five-year period, the samples will be obtained through 18 NHS Trusts, with patients followed up at specific intervals. From late 2019, researchers will be able to apply for access to samples stored in the biobank for future studies.

Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: RENAL AND UROGENITAL
Title: NURTuRE: National Unified Renal Translational Research Enterprise - University of Bristol
Funder: Kidney Research UK

Abstract: NURTuRE: National Unified Renal Translational Research Enterprise - University of Bristol

Lay abstract: The UK Renal Research Strategy recognised the need for a kidney biobank. Kidney Research UK has led the collaboration with industry and academia to launch NURTuRE (the National Unified Renal Translational Research Enterprise) - the first kidney biobank covering England, Scotland and Wales and a key resource for the renal research community. The biorepository is collecting and storing biological samples from 3,000 patients with chronic kidney disease (CKD) and at least 800 patients with idiopathic nephrotic syndrome (INS). It will provide a resource for fundamental and translational research. In addition to the samples of plasma, serum, urine, DNA and tissue that are stored, the repository has the considerable advantage of containing associated linked clinical data, through the UK Renal Registry. Running over a five-year period, the samples will be obtained through 18 NHS Trusts, with patients followed up at specific intervals. From late 2019, researchers will be able to apply for access to samples stored in the biobank for future studies.

Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: RENAL AND UROGENITAL
Title: NURTuRE: National Unified Renal Translational Research Enterprise - UK Biocentre Milton Keynes
Funder: Kidney Research UK

Abstract: NURTuRE: National Unified Renal Translational Research Enterprise - University of Nottingham

Lay abstract: The UK Renal Research Strategy recognised the need for a kidney biobank. Kidney Research UK has led the collaboration with industry and academia to launch NURTuRE (the National Unified Renal Translational Research Enterprise) - the first kidney biobank covering England, Scotland and Wales and a key resource for the renal research community. The biorepository is collecting and storing biological samples from 3,000 patients with chronic kidney disease (CKD) and at least 800 patients with idiopathic nephrotic syndrome (INS). It will provide a resource for fundamental and translational research. In addition to the samples of plasma, serum, urine, DNA and tissue that are stored, the repository has the considerable advantage of containing associated linked clinical data, through the UK Renal Registry. Running over a five-year period, the samples will be obtained through 18 NHS Trusts, with patients followed up at specific intervals. From late 2019, researchers will be able to apply for access to samples stored in the biobank for future studies.

Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: RENAL AND UROGENITAL
Title: PIVOTAL Nurse Contract Year 2 and Year 3 (+ 2 yrs Follow-up Phase)
Funder: Kidney Research UK

Abstract: We have co-ordinated a pioneering clinical trial investigating the optimum amount of intravenous iron that can be given to patients on dialysis to treat anaemia effectively and safely. A complication of being treated for kidney failure using haemodialysis is that patients develop anaemia and iron deficiency. This is a condition that leaves people feeling exhausted and seriously reduces their quality of life. Intravenous iron is a routine part of anaemia management in haemodialysis patients worldwide. However, there has been little evidence to guide optimum dosing, and no consistency in approach across the UK or globally. PIVOTAL was a randomised controlled trial which ran from November 2013 to July 2018, and was designed to address this shortfall in the evidence base. The trial gathered evidence from two different clinical approaches. Some patients were given high doses of iron to increase the levels of iron in their body (proactive high-dose) whilst another group received lower doses of iron only as per normal routine treatment when their iron levels got too low (reactive low-dose). Led by King’s College Hospital in collaboration with Glasgow Clinical Trials Unit, the trial involved 2,141 patients in their first year on haemodialysis and clinicians and research nurses from 50 hospital renal units. It is one of the largest renal clinical trials ever undertaken exclusively in the UK.

Lay abstract: We have co-ordinated a pioneering clinical trial investigating the optimum amount of intravenous iron that can be given to patients on dialysis to treat anaemia effectively and safely. A complication of being treated for kidney failure using haemodialysis is that patients develop anaemia and iron deficiency. This is a condition that leaves people feeling exhausted and seriously reduces their quality of life. Intravenous iron is a routine part of anaemia management in haemodialysis patients worldwide. However, there has been little evidence to guide optimum dosing, and no consistency in approach across the UK or globally. PIVOTAL was a randomised controlled trial which ran from November 2013 to July 2018, and was designed to address this shortfall in the evidence base. The trial gathered evidence from two different clinical approaches. Some patients were given high doses of iron to increase the levels of iron in their body (proactive high-dose) whilst another group received lower doses of iron only as per normal routine treatment when their iron levels got too low (reactive low-dose). Led by King’s College Hospital in collaboration with Glasgow Clinical Trials Unit, the trial involved 2,141 patients in their first year on haemodialysis and clinicians and research nurses from 50 hospital renal units. It is one of the largest renal clinical trials ever undertaken exclusively in the UK.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL
Title: Integrative genomic, epigenetic and functional studies in diabetic kidney disease
Funder: Medical Research Council

Abstract: Diabetic kidney disease (DKD) is a leading cause of kidney failure and end stage renal disease, and brings a substantial burden of early mortality and accompanying health care costs. Genetic factors contribute to the risk of DKD. If we could identify these genetic factors, we could better understand the mechanisms by which DKD occurs, and thereby accelerate the development of better therapies. We established the GENIE consortium, a collaboration between Queen's University Belfast, University of Dublin, University of Helsinki, and the Broad Institute. Together, we completed the largest genetic study to date of DKD, and successfully identified the first two robust genetic risk factors for DKD. In a separately funded genetic study, we are collaborating with additional groups to extend our efforts and encompass larger samples. To better understand the underlying biology and pathophysiology of DKD, we propose to complement and build on our past and ongoing genetic studies in several critical ways. We will leverage a co-funding mechanism between Ireland, Northern Ireland and the US to carry out a multidisciplinary investigation of DKD. We will assemble and jointly analyze all available genetic data pertinent to DKD, to begin the process of discovering rarer variants with stronger effects on DKD. We will also generate DNA methylation data in kidney and blood, and in patients with and without DKD, and also expression data in samples relevant to DKD. We use a novel and powerful method to integrate the genetic, epigenetic and genomic data to generate hypotheses about the biological causes of DKD, and test these hypotheses with further genetic studies (sequencing in a large follow-up sample) and with functional studies in models of DKD. This international, multidisciplinary collaboration will build on genetic discoveries to help decipher the underlying biology and pathophysiology of DKD and thereby guide the prevention and treatment of this important disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: RENAL AND UROGENITAL
Title: Determining the Role of Canonical Notch Signalling in the Regulation of the Glucocorticoid Receptor in Steroid Resistant Nephrotic Syndrome
Funder: Medical Research Council

Abstract: The histological appearance of GS in nephrotic syndrome (NS) can be associated with the development of temporal resistance to glucocorticoid therapy over time. Whether Notch activation is associated with the development of glucocorticoid resistance in GS is currently unexplored. My preliminary data has shown that the glucocorticoid receptor, NR3C1, is expressed in wild-type human podocytes in vitro and in vivo. Furthermore, in primary podocyte cell lines derived from patients with steroid-resistant nephrotic syndrome (SRNS), NR3C1 expression is downregulated compared to that in wild-type control podocytes. As activation of the canonical Notch effector, HES-1, has been previously shown to downregulate NR3C1 and mediate the development of GR in T-ALL, I have determined by immunohistochemistry that HES-1 is temporally upregulated in podocytes of sclerosed glomeruli in kidney biopsy tissue in patients with NS who have been initially steroid sensitive and subsequently developed steroid resistance. These preliminary data support a requirement to investigate further the role of canonical Notch signalling in the development of GR in human NS. I will use a combination of transgenic murine models of GS in addition to cell lines derived from patients with SRNS to examine for Notch pathway activation (gene and protein expression) and determine whether down regulation of the GR and its target genes are coincident with onset of GS and Notch activation. Thereafter I will utilise an inducible murine model of podocyte-specific Notch activation to directly test the role that Notch plays in regulating GR in podocytes. Pharmacological inhibition of Notch will be employed to determine if GR can be rescued in murine models. In parallel, I will utilise next generation sequencing strategies to search for new nephrotic syndrome disease genes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: RENAL AND UROGENITAL
Title: An intravital model to study mechanisms of leukocyte recruitment in experimental crescentic glomerulonephritis (CrGN)
Funder: Medical Research Council

Abstract: The proposed project will use intravital microscopy in a clinically relevant rat model of crescentic glomerulonephritis (CrGN) to study the mechanisms by which leukocytes are recruited to and retained within the glomerulus, through direct visualisation of leukocyte-endothelial interactions in the intact glomerulus in vivo. I will study for the first time the role of leukocyte recruitment in crescent formation and examine the hypothesis that specific subpopulations of blood leukocytes are recruited to discrete areas within the glomeruli, contributing to disease pathogenesis. Importantly, I will investigate the fate of these leukocytes, which may identify clinically useful urinary biomarkers in CrGN. I will use nephrotoxic nephritis (NTN) in the rat as an animal model of CrGN as this model has been extensively characterised genetically and has a histopathological phenotype that closely resembles immune-mediated CrGN in humans. I will use an established WKY rEF1alphaGFP/+ rat to create rEF1alphaGFP+/--WKY rat bone marrow chimeras ("leukocyte reporters"). This will distinguish circulating leukocytes (GFP+) from tissue resident dendritic cells and macrophages. I will use a model of unilateral hydronephrosis to superficialise the glomeruli within the kidney and permit intravital imaging using confocal microscopy. I will study leukocyte trafficking through the glomeruli in steady state and after induction of NTN. Time permitting, I will analyse the urine of rEF1alphaGFP+/--WKY leukocyte reporter rats with NTN using flow cytometry to determine whether GFP+ leukocytes recruited to the glomerulus have a urinary fate. CrGN is an important cause of renal failure and current treatment with generalised immunosuppression is associated with significant morbidity. This work will advance our understanding of the mechanisms of leukocyte recruitment and their role in the pathogenesis of CrGN, facilitating future identification of more targeted therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Models, modifiers and novel treatments of Joubert syndrome
Funder: Medical Research Council

Abstract: We have created a Cep290 mutant mouse model of Joubert Syndrome (JS) that accurately recapitulates human JS, including the variability of phenotype dependent upon genetic background. Furthermore, we have demonstrated that Hh signalling is disrupted in developing renal collecting duct (CDC) cells in these mice and that treatment with a Hh agonist (purmorphamine) can restore normal collecting duct cell function in mutant primary cells ex vivo. The aim of this proposal is to understand the complexity of JS with a view to identifying potential novel therapeutic targets and compounds. This will be achieved by: The identification of genetic modifiers of the murine phenotype. C57BL/6 (severe) mice will be crossed with 129/Ola (mild) mutant mice to generate F2 mice that will be screened (Sequenom) to broadly identify loci associated with severity of cystic kidney disease. Affymetrix gene expression arrays will be used to compare kidneys from the parent strains and from a panel of F2 mutant mice to highlight potential modifier genes within these loci. The identification of novel disease alleles mutated in JS patients. Synentic regions in JS patients having undergone whole exome sequending will be compared with the corresponding to the candidate loci identified in mice. This approach will also serve to validate candidate genes found in mice. Functional assessment (loss/gain of function) of modifier genes in primary CDCs from JS mice and patients. The effects of loss-of-function (siRNA knockdown) and/or gain of function (lentiviral overexpression) will be evaluated in primary cells from our mouse model and ultimately in JS patient CDCs. The effects of these modifier genes will be assessed in terms of Hh agonist rescue. This project will address the issue of phenotypic heterogeneity in JS and determine the effects of this heterogeneity upon drug efficacy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Collectin-11 as a trigger of the innate immune response in renal transplantation
Funder: Medical Research Council

Abstract: Collectin-11 (CL-11) is a collagen-containing lectin molecule that recognises carbohydrate residues on pathogen surfaces and mediates pathogen elimination. As a trigger for complement activation, CL-11 is likely to have pathological functions induced by non-infectious agents, but this remains to be shown. Given the high basal expression of CL-11 in the tubulo-intestinal compartment of the kidney, CL-11 could be a local trigger involved in renal ischaemia-reperfusion injury, which we have shown is strongly complement-dependent and a cause of accelerated transplant loss. In support, we have generated evidence in CL-11 deficient mice of protection from the effects of ischaemia-reperfusion insult. We also find that cultured renal tubular epithelial cells bind CL-11 following cellular stress. We propose that carbohydrate ligands (very likely L-fucose) on the tubule cell surface or glycocalyx coat are exposed by cell stress and cause attachment of CL-11. We anticipate that cell-bound CL-11, which is known to form a complex containing the proteolytic enzyme MASP-2, induces lectin-pathway mediated cleavage of C3, thereby releasing effector products with known inflammatory and pro-fibrotic functions. The proposed experiments using knockout-mice and biochemical analysis of CL-11 interactions on cultured renal tubule cells should solve a puzzle concerning how the destructive mechanism mediated by C3 on the renal tubule surface is initiated. Placing CL-11 on the path between oxidative stress and epithelial inflammation will create new opportunities to track and block these interactions for patient benefit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Aldosterone-induced endothelial glycocalyx dysfunction, a potential therapeutic target in proteinuria?
Funder: Medical Research Council

Abstract: Hypothesis- Aldosterone acts on glomerular endothelial cells (GEnC), to initiate a chain of biochemical events that result in damage to the endothelial glycoclayx (Glx) and proteinuria. Research objectives 1. Demonstrate aldosterone disrupts the GEnC Glx with functional effects including increased protein permeability 2. Confirm this effect is dependent on the direct action of aldosterone on GEnC 3. Review if GEnC Glx disruption is caused by heparanase release from GEnC Methodology- Human conditionally immortalised glomerular endothelial cells (CiGEnC) will be used in vitro. Glx response to Ald, and protection by heparanase inhibition will be assessed by immunofluorescence (IF) of key Glx components, shear stress sensitivity and Glx permeability to FITC-labeled BSA. In vivo aldosterone exposure will be assessed using osmotic minipumps to administer 0.6micg/g/day aldosterone to FBV/N mice to render them proteinuric by 4/52. Glomerular endothelial MR knock out mice (Tie2-rtTA, Tet-O-Cre, MRflox/flox mice) will be used to confirm these effects are due to GEnC MR receptors. Outcome measures will include proteinuria and Glx damage. Glx will be directly visualised and permeability assessed using multiphoton microscopy.2 Immunofluorescence will be used to quantify key glomerular Glx components and electron microscopy used to assess alterations in Glx thickness. Spironolactone and SST0001 (specific heparanase inhibitor) will be used to confirm the roles of MR/heparanase in the process. Opportunities- Proteinuria places patients at high risk of progressive kidney disease and systemic vascular disease. Proteinuria results from a failure of the glomerular filtration barrier of which the Glx is a vital part. Ald has been shown to cause proteinuria and damage the Glx in vitro. Clarifying the effects of Ald in vivo and mapping a pathway potentially amenable to pharmacological intervention could provide a novel series of therapeutic targets for future research.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL