NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the cellular and microvesicle content of human urine in health and disease
Funder: The Academy of Medical Sciences

Abstract: Human urine contains a diverse content beyond just ions, toxins and water. There is an abundance of microvesicles such as exosomes within urine originating from cells from across the entire nephron. These contain proteins and nucleic acid from the cell of origin that can be used to easily and non-invasively assess the health of the kidney. Some of these microvesicles originate from the large immune content of the kidney that has relevance to common important diseases such as acute kidney injury, chronic kidney disease, diabetes and urinary tract infections and also significant but rarer conditions including renal autoimmune diseases like vasculitis and glomerulonephritis. It is possible to find immune cells within the urine of completely healthy individuals but the purpose and origins are unclear. By better understanding both urine microvesicles and cells we can gain insight into renal and urinary tract physiology, pathology and develop non-invasive biomarkers of these processes which are currently lacking. Aims: 1. Isolate and characterise the microvesicles in healthy human urine 2. Isolate and phenotype the cellular content of healthy human urine 3. Understand how both micovesicles and cells vary in healthy humans e.g by circadian rhythm, gender and age 4. Isolate and characterise the microvesicles and cells in common important renal disease processes

Lay abstract: Kidneys clean the blood removing toxins and excess water. This can go wrong in many ways and can lead to patients needing an artificial kidney machine (dialysis) or a kidney transplant. Kidney failure causes a significant impact on the wellbeing and life expectancy of patients. Despite its importance there are very few investigations available to doctors to identify the cause of kidney disease. The best investigation currently is a kidney biopsy where a needle takes a sample of the kidney, this is not without risk, 1 in 10 patients get bleeding after this procedure which may be so severe it requires an operation or very rarely can cause death. Urine contains many components of kidney cells and some of the cells of the immune system, these seem to change between healthy people and those with kidney disease. By characterising these in the urine I aim to understand the differences in health and disease. This should lead to better understanding of how healthy kidneys work, how this goes wrong in diseases and lead to new and better tests for kidney disease that are easier, quicker and won't pose any risk to patients.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Nanocomplex therapy for childhood kidney disease
Funder: LifeArc

Abstract: This project aims to develop a new treatment for children with a rare genetic kidney syndrome called Denys-Drash syndrome (DDS) – improving the outlook for affected children and their families. Children born with DDS will develop kidney disease in the first few months of life. This damage will usually rapidly worsen, leading to complete kidney failure in early childhood. Children living with DDS will then need life long dialysis while they wait for a transplant. DDS is caused by damage to kidney cells responsible for filtering waste from the blood. Unfortunately, there are currently no effective treatments that can help slow down or stop this damage. The researchers have designed a new treatment for DDS, which aims to boost the activity of a protein called angiopoietin-1 and help protect the kidneys from damage. By packaging the new therapy into tiny balls of fat, they hope to reduce the chance of the kidneys removing it from the body – and they have also attached a small protein fragment to target it specifically to the affected kidney cells. The team will now test their new treatment in a laboratory model of DDS – delivering it using a unique technique involving ultrasound scanning to guide an injection directly into the kidney’s blood supply. Their results will establish the effectiveness of this novel delivery method and determine if their treatment can help slow or stop kidney damage in this disease model.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL
Title: Development of a risk model for the prediction of new or worsening Acute Kidney Injury (AKI)
Funder: Department of Health (England)

Abstract: Acute kidney injury (AKI) is a global health issue. Its prevalence (5-7% amongst hospitalized patients [1420]) is increasing. [2122] A patient with Acute Kidney Injury Network stage 3 (AKIN3; a >3 fold rise in serum creatinine (SCr) from baseline) has a 23 fold risk of in-hospital mortality 199% increase in length of stay 26 fold risk of ITU admission 27% 30 day re-admission rate a 7% increase in care on discharge and 5 fold risk of 12 month mortality compared to a patient that did not experience AKI (our preliminary work - AKI audit in East Kent - presented: Joint British Renal Society / Renal Association Conference (June 2011) and EQ AKI Pathway launch (October 2011)). Even for smaller rises in SCr outcomes are significantly worse. AKI is often preventable and reversible. All hospitalised patients are at risk. It is essential AKI is recognised early and treated effectively however the 2009 National Confidential Enquiry into Patient Outcome and Death (NCEPOD) highlighted systematic failings of identification and subsequent management and recommended risk assessment for AKI in all emergency admissions.[21] The AKI Working Group (NHS Kidney Care Department of Health) development of the NICE AKI Guideline and adoption of AKI in the Enhancing Quality (EQ) framework aim to address this problem. From this basis we aim to deliver a validated risk assessment that is transferable across the NHS and determine the most effective way to integrate this into everyday clinical practice. This will prepare the ground work for the followup to this study in which we will develop the risk assessment algorithm into a clinical decision support system (CDSS) to alert and provide recommendations at the point of care. This will develop a predictive model (a Bayesian approach) to identify patients at risk of AKI or of worsening AKI and quantify risk in order to stratify patients. This risk model will be incorporated into a mathematical algorithm which will incorporate risk factors identified in GP and hospital computer records and admission characteristics of each patient. We will validate the developed risk model in the East Kent population but also in a second population and NHS Trust to both ensure the validity of the risk assessment but also ensure transferability across the NHS. Using qualitative focus group methodology we will then determine the most effective way to integrate the alert / outcome of the risk assessment into everyday clinical practice. This project will significantly improve clinical practice patient safety and education in management of AKI. We will inform clinical guidelines and audit pathways of AKI and allow focusing of care. Our work is in line with national policy and fulfils important recommendations of the NCEPOD.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: RENAL AND UROGENITAL
Title: Long-term tapering versus standard prednisolone (steroid) therapy for the treatment of the initial episode of childhood nephrotic syndrome: national multicentre randomised double blind controlled trial
Funder: Department of Health (England)

Abstract: PREDNOS is a UK multi-centre double blind randomised controlled trial. The aim of the trial is to compare an extended course (sixteen week) tapering prednisolone regimen with the standard eight week regimen as originally proposed by the International Study of Kidney Disease in Children (ISKDC). The primary study objective is to determine whether an extended course of prednisolone increases the time to first relapse in children presenting with steroid sensitive nephrotic syndrome. The standard course of therapy (eight weeks) is: Weeks 1 - 4 Prednisolone 60mg/m2/day (max 80mg) Weeks 5 - 8: Prednisolone 40mg/m2 (max 60mg) on alternate days for 28 days. This will be compared with an extended course of therapy (sixteen weeks): Weeks 1 - 4 Prednisolone 60mg/m2/day (max 80mg) Weeks 5-16: Prednisolone 60mg/m2 (max 80mg) on alternate days tapering by 10mg/m2 every 2 weeks.Recruitment and randomisation will occur during the initial four week open label treatment during which all children will be treated in accordance with existing national protocols with prednisolone 60mg/m2 (maximum 80mg) daily in an open label manner to ascertain whether they are steroid sensitive and as such eligible for recruitment into the study. The randomised study drug regimen will commence at day 29. The study is double blinded through the use of prednisolone 5mg and matching placebo tablets and children in both treatment arms will receive the same number of tablets at any time-point in the study. Recruitment will take place over a period of two years. All patients will be followed up for at least 24 months and for a variable time period beyond 24 months until 2 years following the recruitment of the last patient.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL
Title: The relationship between pelvic vein incompetence and chronic pelvic pain in women: an evidence synthesis
Funder: Department of Health (England)

Abstract: Chronic pelvic pain (CPP) is a common and debilitating symptom in women of childbearing age with a negative impact on quality of life. CPP can be a condition in its own right or associated with conditions such as endometriosis adhesions and pelvic congestion syndrome (PCS) this makes establishing a diagnosis often problematic leading to a delay in appropriate treatment. PCS defined as the presence of varices of the pelvic veins has been shown to be the underlying aetiology in a significant proportion of patients with CPP.The project will systematically and critically review the evidence regarding the relationship between radiological observations of dilated and/ or refluxing pelvic veins angiographic observations and the symptoms of chronic pelvic pain and review the effectiveness of pelvic vein embolisation/ schlerotherapy for PCS. Collection of individual patient data (IPD) from available studies involving embolisation/ schlerotherapy will enable us to identify factors associated with successful outcome and perform IPD meta-analysis if possible.Anticipating uncertainty from the data regarding the effectiveness of embolisation/schlerotherapy we will attempt to establish whether equipoise exists in clinical community and any differences between UK European and international clinicians through both a survey of current practice and elicitation of prior beliefs using Bayesian methods. This will establish whether a randomised controlled trial is both feasible and desirable.


Research activity codes: 6.3 MEDICAL DEVICES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL
Title: Targeting sensory neurons to restore bone marrow regenerative potential in diabetes
Funder: Medical Research Council

Abstract: In diabetic patients, circulating progenitor cells (PC) are reduced and accumulate epigenetic changes that compromise their function. Our overarching hypothesis is that diabetes reduces the regenerative potential by affecting PC in the bone marrow (BM) niche. We showed that microangiopathy affects the BM of diabetic animals, creating a harsh microenvironment incompatible with PC homeostasis. We now propose that another common complication, e.g. sensory neuropathy, impinges on BM homeostasis and compromises the egression of regenerative PC upon ischaemia. Although it is known that diabetic patients suffer silent ischemia, due to altered heart innervation, the possibility that sensory neuropathy extends to BM was not investigated. Pilot data indicate that sensory fibres are present in BM together with PC that express neuropeptide receptors. Exposure to neuropeptides enhances PC motility and allows isolation of PC endowed of potent proangiogenic activity. Furthermore, this sub-fraction is enriched within the cell population mobilized after myocardial infarction in non-diabetic patients. Neuronal fibres are reduced in diabetic BM, this defect being associated with blunted response of marrow PC to neuropeptides and decreased nerve growth factor (NGF), which is essential for sensory nerve function/regeneration. This project aims to: 1.Characterize structural alterations underpinning the impaired neuronal control of PC mobilization, 2.Unravel the molecular mechanisms of this deficit and 3.Restore neurotrophic signalling by targeted delivery of NGF to neuronal cells thereby rescuing BM capacity to respond to noxious stimuli. We will also investigate if NGF adds to the protection afforded with metabolic control. Therefore, this proposal has the twofold ambition to clarify key mechanisms of diabetic complications and translate this knowledge into new therapies for devastating complications insufficiently controlled by current treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: RENAL AND UROGENITAL
Title: The role of podocyte thymosin-beta4 in the healthy and diseased glomerulus
Funder: Medical Research Council

Abstract: Research objectives: The objectives of these studies are (i) to determine the role of podocyte thymosin-beta4 in the developing and mature healthy glomerulus using transgenic mice and cultured cells. (ii) determine if modulation of thymosin-beta4 attenuates progression of glomerular disease, hence raising the possibility that thymosin-beta4 could improve the health of kidney patients. (iii) assess the relative contribution of podocytes and other renal sites of thymosin-beta4 in the progression of glomerular disease. Experimental Design: I will utilise global null-mutants and specific knock down of thymosin-beta4 in the podocyte using floxed thymosin-beta4 animals bred with doxycycline inducible podocyte-specific Cre recombinase mice and will assess changes in the structure and molecular biology of the glomerulus. Moreover, using the above transgenic animals, I will determine whether lack of thymosin-beta4 alters progression of immune-mediated and adriamycin-induced glomerular diseases. These are good models of human pathologies and it will be important to identify how the balance of thymosin-beta4 in different parts of the kidney affects the course of disease because this will influence how targetted therapies need to be developed. Application and Exploitation: My studies will define the function of thymosin-beta4 in the kidney glomerulus which will lead to high-impact publications in scientific journals. In addition, it could lead to the design of new therapies for human renal disease. If this is the case, then thymosin-beta4 has the potential to impact on society by improving the quality of life of patients with kidney disease as well as a major economic impact by reducing the number on expensive dialysis regimens or needing a kidney transplant.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Understanding the autoimmune mechanism in idiopathic membranous nephropathy (IMN)
Funder: Medical Research Council

Abstract: The objectives are 1) to understand how DQA1 and PLA2R genes control quantity and specificity of anti-PLA2R production in IMN patients to induce proteinuria 2) to identify specific peptides in the target antigen that define B cell and T cell epitopes 3) to identify additional genetic factors that promote and maintain anti-PLA2R levels to cause disease progression 4) to characterise the natural immune regulatory control mechanism that switches off anti-PLA2R production and induces spontaneous remission We already have GWAS SNP data and anti-PLA2R levels on 556 patients with IMN and will obtain clinical outcome data on these patients. In addition, we will sequence DNA on 200 cases of PLA2R positive MN who have progressed to CKD5 and who have been transplanted (samples collected through collaboration with UK Transplant Labs) This will enable us to test for genetic markers associated with high and low anti-PLA2R production and genes that predict disease progression. We will sequence DQA1 and PLA2R genes in the donor for each donor recipient pair so that we know the genetic changes that occur at transplantation. Through classification of the transplant outcome at 5 years (proteinuria, anti-PLA2R status and/or biopsy) we can define recurrent and non-recurrent disease. In this natural experiment of genetic change we will test the validity of our genetic markers for high antibody production as predictors of disease and anti-PLA2R post transplantation. We have identified a strategy of trypsin digestion of recombinant PLA2R and western blotting of fragments followed by mass spectrometry analysis to identify B cell epitopes. Bioinformatics predicts PLA2R peptide sequences binding to pathogenic DQA1 alleles


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: The role and regulation of Hepatocyte Nuclear Factor-1 Beta in man
Funder: Medical Research Council

Abstract: Aims and objectives: 1) To study phenotypic variation in patients with Hepatocyte Nuclear Factor-1 Beta (HNF1B) mutations, as well as develop biomarkers to aid diagnosis. 2) To extend genetic studies to define regulatory and non-coding HNF1B mutations. 3) To identify novel genes involved in renal development. Methodology: -Phenotypic variation in patients with HNF1B mutations will be studied. We will also assess 3 potential biomarkers (magnesium; urate; faecal elastase and pancreatic exocrine function) to distinguish HNF1B developmental kidney disease from other forms The sensitivity and specificity will be determined by testing 100 patients with 100 age- and sex-matched controls. -To explore the possibility of intronic, promoter and regulatory mutations of HNF1B, long-range PCR products will be generated from patients who are HNF1B negative but have a phenotype that is highly suggestive and undergo next generation sequencing. -Exome sequencing will be used to identify novel causes of renal developmental disorders. Important outcomes from this project should include: -Improvements in diagnosis through integration of diagnostic clinical criteria with biomarkers. -Advancements in genetic analysis following extended analysis of the regulatory regions of HNF1B. -Development of novel genetic tests for developmental renal disease.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: The role of filtered IgA in the progression of IgA nephropathy
Funder: Medical Research Council

Abstract: IgA nephropathy (IgAN) is the commonest primary glomerular disease, and a leading cause of end stage renal failure worldwide. The strongest predictor of progressive kidney disease in IgAN is the development of tubulointerstitial inflammation and fibrosis. The development of non-selective proteinuria, occurring when high molecular weight proteins including immunoglobulins escape through the damaged glomerular filtration barrier, is thought to be a fundamental trigger for fibrosis, stimulating release of pro-inflammatory and pro-fibrotic mediators by proximal tubular epithelial cells (PTEC) into the renal interstitium. The presence of immunoglobulins in the urine has traditionally only been used as a marker of severity of glomerular injury, with little work done on their direct pathogenicity. My preliminary data shows that IgA is able to exert a potent effect on PTEC, favouring development of a pro-inflammatory and pro-fibrotic tubulointerstitial microenvironment in non-selective proteinuria. I will test the hypothesis that "A major factor determining the development of progressive renal failure in IgAN is the presence in the serum of IgA1 with PTEC-specific pro-inflammatory and pro-fibrotic activity. As non-selective proteinuria develops this IgA1 enters the urine and augments PTEC activation, accelerating renal scarring". My aims are to: 1. Detail key biochemical pathways activated by IgA1 in PTEC. 2. Characterise key receptors activated by IgA in PTEC, focussing on the role of the multi-ligand scavenger receptor megalin. 3. Study the role of candidate scavenger receptors in an in vivo model of IgAN. 4. Translate the above findings to human disease, utilising our bank of serum, urine and biopsy samples to perform in vitro and immunohistochemical studies. These studies will provide new insights into the mechanisms by which filtered IgA may play a role in driving tubulointerstitial fibrosis in IgAN, and thus potentially reveal novel therapeutic targets


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Functional testing of kidneys tissue-engineered from renogenic stem cells.
Funder: Medical Research Council

Abstract: This proposal addresses a priority area of MRC-MCMB: tissue engineering for regenerative medicine. It will test the physiological function of 'kidneys' tissue-engineered by a method developed in this lab: an important step in closing the gap between cultured stem cells and transplantable organs. We have published a 2-step technique that turns suspensions of embryonic kidney stem cells into all of the epithelial and mesenchymal structures of a typical foetal kidney (Bowman's capsule, proximal and distal tubule, collecting duct, stroma etc), arranged and connected correctly, and we have pilot data showing that these engineered kidneys will become vascularized and will filter blood when transplanted into an adult host. We now wish to test, robustly and quantitatively, their functional ability: 1) We will add endothelial cells, grafted vessels in normal culture, and chick endothelia in chorioallantoic membrane (CAM) culture, to assess the ability of engineered kidneys to construct an anatomically-correct blood system. 2) We will use the fact that blood will be flowing in the CAM system (powered by the chick embryo heart) to test glomerular filtration using a standard labelled tracer method. 3) We will test active transport of organic anions and cations in the proximal tubules using labelled tracers: this will not depend on the success of parts 1 and 2 because it does not require flowing blood. 4) We will assess the robustness of the engineering system and its ability to self-correct deliberately-introduced errors of cell balance and arrangement. We have theoretical grounds to expect this. Overall, this proposal advances our existing re-creation of basic renal anatomy to determining functional attributes. Afterwards, if the engineered organs perform as well as we expect, we can justify testing their ability to substitute for natural kidney function when matured in adult hosts. The self-organization based technology has more general biotech implications.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: RENAL AND UROGENITAL
Title: An integrative genomics approach for non-invasive diagnostic biomarkers discovery in IgA nephropathy
Funder: Medical Research Council

Abstract: A) Family-based and population-based linkage analysis B) Identification of quantitative trait loci (QTL) responsible for deglycosylated IgA1 serum levels; C) Stratification using susceptibility genetic variants (HLA haplotypes, structural variants across the CFH-CFHR); D) Resequencing through NGS of a selected subsample of informative families E) Variants Validation F) Identification of biomarkers for IgAN and Bayesian Model


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