NIHRDataInsights/HRCSData huggingface dataset:
Title: Lymphatic biology in kidney development, health and disease
Funder: Wellcome Trust

Abstract: The lymphatic vasculature is essential for health in vertebrates. Alongside roles in tissue fluid balance, cholesterol transport and immunomodulation, lymphatic vessels possess remarkable organotypicity, which underpins organ-specific lymphatic functions during embryonic development, health and disease. Using the mammalian kidney as a model system, I will study two concepts responsible for the organotypicity of lymphatics: the cellular sources of lymphatic endothelial cells and molecular crosstalk between lymphatics and epithelia, a paradigm that may be applicable to other organs like lung and gut. I will focus on these processes in embryonic development, health and polycystic kidney disease (PKD); the most common genetic renal disorder, which features dysfunctional lymphatics. I will use several emerging technologies including high-resolution three-dimensional imaging, single-cell RNA sequencing, novel in vivo imaging modalities, targeted kidney delivery of therapeutics and computational modelling. The insights arising from these experiments in this Investigator Award will enhance our understanding of lymphatic biology in kidney development, physiology and disease; areas in which the contribution of lymphatics is poorly understood. The findings will provide new directions and tools for understanding and manipulating lymphatic function in organogenesis, health and multiple disease processes.

Lay abstract: This work will examine how specialised tubes called lymphatic vessels, which clear away excess fluid, immune cells and debris, grow, work and ‘talk’ to other cells in growing or diseased organs. Defects in lymphatics are linked to common and major diseases including heart attacks, obesity, dementia, cancer and kidney disease. The development of novel treatments for this wide range of diseases would be greatly benefitted by a better understanding of how lymphatic vessels grow and communicate with other cells. By studying the kidney as an example, I will use sophisticated technologies, capable of three-dimensional imaging and reading genes at cellular detail, to discern how lymphatic vessels grow and communicate with neighbouring cells in the kidney. I will examine how these processes are impaired in polycystic kidney disease; the most common genetic renal disorder and will attempt to restore them to normality by using a lymphatic-based therapy directed to the kidney.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: RENAL AND UROGENITAL;GENERIC HEALTH RELEVANCE
Title: MICA - DEfining MechanIsms Shared across mulTI-organ FIbrosis to prevent the development of long-term multi-morbidity DEMISTIFI-Multi Morbidity
Funder: Medical Research Council

Abstract: Ammended Technical Summary: Organ fibrosis accounts for one third of all deaths world-wide. It is associated with aging and metabolic abnormalities that occur in response to many genetic and environmental factors. Understanding shared pathogenic mechanisms may identify clusters of disease that will respond to repurposing of available therapies. Common genetic, environmental, lifestyle and socioeconomic factors or biological pathways linking these clusters aren't readily recognised by conventional disease centred approaches. Focusing on the mechanistic basis of fibrosis offers a unique opportunity to recognise early disease, identify disrupted mechanisms and repurpose drugs which target the underlying pathological process. Our vision is to identify clusters of multi-organ fibrotic diseases, referred to as Fibrotic Multi-Morbidity (FMM), with common pathogenic mechanisms that will benefit from shared management strategies, reducing the burden of treatment through therapeutic rationalisation, early identification of secondary organ involvement, and appropriate risk reduction strategies to increase the health-span of this group of patients. We will achieve this vision by using Magnetic Resonance Imaging to identify clusters of FMM and measure total body fibrosis to generate a Fibrotic Multi Morbidity Score (FMMS) for use in observational and interventional clinical trials. We will analyse large longitudinal datasets such as UK Biobank and the Clinical Practice Research Datalink as well as in a range of deeply phenotyped organ specific cohorts to identify genetic risks and environmental factors that predispose to FMM, and associate these factors with important clinical outcomes such as disability and premature death. Through understanding the clusters of Fibrotic Multi-Morbidity and mapping them to the mechanisms of available therapies, the DEMISTIFI consortium will aim to prevent the development of long term Fibrotic Multi-Morbidity.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: RENAL AND UROGENITAL;GENERIC HEALTH RELEVANCE;ORAL AND GASTROINTESTINAL
Title: Development of a sustainable urinary continence management device to help reduce covid-19 infection risk
Funder: Innovate UK

Abstract: This project will complete the development of a novel urinal that enables elderly and infirm users to urinate unaided whenever the need arises, thus increasing their independence and dignity. Although designed specifically for female users, the device is unisex and suitable for all ages. Key user benefits include: * Ease of use for those with restricted physical mobility, reduced manual dexterity (for example, arthritis sufferers) and those with impaired vision; * Convenience and compostability - it's pocket-size, there's nothing to clean, and after use it can be disposed of as green waste; * Reduced call on carers' time to assist with loved ones toileting needs. The design has been developed with significant input from incontinence sufferers and experts and addresses an area of significant unmet need. In addition, the project will undertake prelimiary development work and prototyping of a product variant for the consumer/leisure market.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: RENAL AND UROGENITAL;INFECTION
Title: The role of the factor H-related proteins in kidney disease
Funder: Wellcome Trust

Abstract: The complement factor H-related (FHR) proteins influence susceptibility to kidney and eye (age-related macular degeneration) disease, and to meningococcal infection. The FHR proteins are related to complement factor H (FH), the major negative regulator of complement C3 activation. Unlike FH the biological roles of the FHR proteins remain unclear. Understanding how FHR proteins damage the kidney is very important because they are associated with both rare (C3 glomerulopathy) and common (IgA nephropathy) kidney diseases that lack effective treatments. My key goals are to determine how FHR proteins mediate renal injury and if modulating FHR activity can reduce complement-mediated kidney injury. My experimental program will utilise novel mouse strains, developed during my current fellowship, to determine if absence of FHR proteins reduces kidney injury in experimental nephritis, including IgA nephropathy. I will characterise the mechanisms through which mutant FHR proteins cause C3 glomerulopathy by detailed phenotyping of the first model of FHR-associated C3 glomerulopathy. I will elucidate the mechanism through which accumulation of glomerular C3 causes kidney injury. My program will help us to understand how to manipulate these proteins therapeutically which I predict will reveal a means of modulating complement that is safe and amenable to long-term therapy.

Lay abstract: Complement refers to a group of proteins that we use to fight infection. Complement is very efficient at killing bacteria. However, under some circumstances complement can cause damage to our tissues. The kidney and eye are very susceptible to damage by complement. Complement contributes to kidney damage in both rare and common kidney disease. C3 glomerulopathy is an example of a rare kidney disease caused by complement. It affects children and young adults and can cause permanent kidney damage which then necessitates either dialysis or a kidney transplant. A common condition in which complement contributes to kidney damage is IgA nephropathy. For both C3 glomerulopathy and IgA nephropathy there is currently no effective treatment. My research program studies how complement causes kidney damage in both these diseases. My aim is to use these findings to develop safe treatments that will prevent complement from causing kidney failure.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: US-Ireland R&D Partnership - Integrative genomic, epigenetic and functional studies in diabetic kidney disease
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) worldwide. Although excellent long-term control of blood glucose ca n decrease the risk of diabetic kidney disease, many patients with adequate control of diabetes will still develop nephropathy, while others remain complication-free despite poor blood glucose control. Family studies point to a strong role for inherited factors in the development of nephropathy, but the relevant genetic variants remain unknown, limiting our understanding of this devastating complication. Our long term goal is to discover the genetic and epigenetic factors that influence the risk of diabetic nephropathy, with the hope that improved understanding of the kidney disease will identify novel diagnostic markers and biological targets for therapeutic and preventive intervention. The GEnetics of Nephropathy - an International Effort (GENIE) Consortium have recently completed the largest genome wide association study (GWAS) to date and meta-analysis of nephropathy and ESRD in type 1 diabetics. We plan to build on these novel data by discovering rare genetic variants that are highly protective or strongly deleterious fir diabetic nephropathy and to assess the functional consequences of such variants by exploiting our established diabetic kidney disease model systems. We will perform a genome wide exploration for epigenetic marks in diabetic kidney disease and mine GWAS datasets for enrichment of signals via pathway analysis and integration of existing datasets. These investigations, conducted by an international research consortium, will define the mechanisms underlying genetic susceptibility to diabetic nephropathy and facilitate the identification and development of new biomarkers and therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL;METABOLIC AND ENDOCRINE
Title: The role of heterotypic cell-to-cell communication in mediating inflammation and fibrosis in the diabetic kidney
Funder: Diabetes UK

Abstract: Connexins (Cx) are membrane bound proteins, which align with those on neighboring cells to form gap junctions, or work independently as hemi-channels to signal via paracrine-mediated release of ATP. Altered connexin expression has been linked to multiple pathologies of secondary complications of diabetes, yet we know nothing for the role for connexins in the proximal region of the diabetic kidney, where expression is high and tubulointerstitial fibrosis represents the key underlying pathology. Preliminary data confirms that isoforms Cx26 and Cx43 exhibit aberrant levels of expression in biopsies obtained from patients with diabetic nephropathy and in glucose treated human proximal tubule cells (hPTECS). These altered levels of expression are paralleled by loss of Gap Junction Intercellular Communication (GJIC) and increased hemi-channel mediated ATP release. Elevated levels of ATP have been linked to inflammation and fibrosis and we hypothesize that aberrant Cx43 activity acts as a stimulus to initiate activation and recruitment of resident PTECS, fibroblasts and infiltrating macrophages. We will work with industrial and clinical colleagues to utilize novel therapeutic compounds to investigate the hypothesis that Cx43 mediated hemi-channel ATP release represents a future therapeutic target for treatment of diabetic nephropathy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL;METABOLIC AND ENDOCRINE
Title: Investigating and improving signs and symptoms of chronic kidney disease through a dietetic-led integrated model of care in older people nearing end stage renal disease with the aim of improving patient-centred and medical outcomes in a cost efficient manner.
Funder: Department of Health (England)

Abstract: Dialysis is increasingly used to treat older people with end stage renal disease (ESRD), often for life. The aims are twofold: to describe physical and psychological changes that affect older people approaching ESRD; to improve the medical, quality of life and healthcare cost outcomes (including delaying need for dialysis) through dietetic-led input with nursing and medical care. This will be investigated in two ways: questionnaires delivered over two years to a group of participants; dietetic-led care to a smaller group whose outcomes will be compared to patients receiving standard care. Change in patient-centred, medical and economic outcomes will be assessed.


Research activity codes: 7.2 END OF LIFE CARE;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: RENAL AND UROGENITAL;ORAL AND GASTROINTESTINAL
Title: A multi-omics study to dissect the role of the gut microbiome in IgA nephropathy risk
Funder: The Academy of Medical Sciences

Abstract: Immunoglobulin A (IgA) nephropathy (IgAN) is the most common form of glomerulonephritis, with high prevalence in both Chinese and European populations. IgAN can be mild, or progress to kidney failure in up to 40% of patients within 20 years. Its pathogenesis has not been fully described, but the fact that IgAN can recur after transplantation hints to a systemic condition caused by factors external to the kidney itself. Recently, mucosal immunity and gut microbiome have been suggested to participate in the pathogenesis of IgAN. In this project, we will investigate the role of the gut microbiota in mediating the gut-kidney dialogue in IgAN also via the IgA glycome, which plays a crucial role both in mucosal immunity, especially in the gastrointestinal tract, and in the disease initiation and progression. We will take advantage of three well-characterized samples, including IgAN patients and controls from China and the UK, to: 1.identify microbes and microbial functions (i.e., microbial genes and metabolic pathways they participate to) associating with IgAN and/or with IgA1 and galactose-deficient IgA1 (gd-IgA1) levels; 2.functionally characterize, in a sample of healthy controls and IgAN patients, microbes and microbial functions identified in the previous steps by means of a set of multi-omics in silico analyses; and 3.validate, in vivo, via faecal microbiota transplantation in mouse models, the role played by the gut microbiota in IgAN.

Lay abstract: Bacterial infection may stimulate the mucosa immune response, resulting in an overproduction of IgA, and in the past few years, several studies have suggested the presence of a gut-kidney dialogue in IgAN. We anticipate that, due to differences in the genetic make-up as well as in lifestyle factors between our two samples, they may show different microbial taxonomic profiles. For instance, some microbial species detected in the Chinese sample may not be present in the UK one. However, we are confident that microbial functions, defined as microbial genes and metabolic pathways they participate in, will only be marginally affected by these differences. Indeed, using microbial genes, rather than taxonomic profiles, has already been shown to be a promising approach for the identification of shared signatures of microbial dysbiosis for colorectal cancer in Chinese and Europeans cohorts.The project aims at discovering microbes and microbial functions associated with IgAN and/or IgA1 and gd-IgA1 profiles, which will be functionally characterized in the second phase via in silico and in vivo experimentations.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: RENAL AND UROGENITAL;ORAL AND GASTROINTESTINAL
Title: Difelikefalin for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adult patients receiving in-centre haemodialysis [ID3890]
Funder: Department of Health and Social Care

Abstract: Pruritus, or itch, commonly affects people with chronic kidney disease. It is a chronic, unpleasant symptom that can have a strong negative impact on people’s quality of life, often leading to sleeplessness and mood disorders, including depression. The itching can be localised or generalised. When localised, it often occurs in the back, face, and arm. The urge to scratch can result in skin abrasions. It is also associated with a 17% increase in mortality in people having haemodialysis. [1] The prevalence of moderate to severe pruritus in people having haemodialysis in the UK has been estimated to be around 50%. [2] Applying this estimate to data from the most recent UK Renal Registry report suggests that there are about 10,000 people having haemodialysis and with moderate to severe pruritus in the UK. [3]_x000D_ _x000D_ There are currently no approved treatments for pruritus associated with chronic kidney disease, although treatments for other conditions are sometimes used off label, such as the gamma aminobutyric acid (GABA) analogues gabapentin and pregabalin._x000D_ _x000D_ References_x000D_ _x000D_ 1) DermNet NZ. Uraemic Pruritus. 2010. Available from: https://dermnetnz.org/topics/uraemic-pruritus/. Accessed February 2021._x000D_ 2) Rayner HC, Larkina M, Wang M, Graham-Brown M, van der Veer SN, Ecder T, Hasegawa T, Kleophas W, Bieber BA, Tentori F, Robinson BM. International comparisons of prevalence, awareness, and treatment of pruritus in people on hemodialysis. Clinical journal of the American Society of Nephrology. 2017 Dec 7;12(12):2000-7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718267/ Accessed February 2021._x000D_ 3) UK Renal Registry. UK Renal Registry 21st Annual Report – data to 31/12/2017, Bristol, UK. . 2019. Available from: https://www.renalreg.org/publications-reports/ Accessed February 2021.

Lay abstract: To appraise the clinical and cost effectiveness of difelikefalin within its marketing authorisation for treating pruritus associated with chronic kidney disease in adults having haemodialysis.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL;SKIN
Title: MICA: Evaluation of the selective endothelin A-receptor antagonist zibotentan as a treatment for renal disease in systemic sclerosis (scleroderma)
Funder: Medical Research Council

Abstract: Although uncommon, systemic sclerosis (scleroderma: SSc) is important because of its unmet medical need and high burden of complications, with more than half of patients dying as a direct result of SSc. Endothelin (ET-1) is implicated as a pathogenic mediator in SSc; elevated circulating levels of ET-1 occur in SSc-associated pulmonary arterial hypertension (PAH-SSc) and in SSc renal crisis (SRC). ET-1 antagonists are an approved therapy for PAH and for ischaemic digital ulceration in SSc, and may have major benefit in treating important renal complications of SSc; however, this has not been adequately addressed. Renal manifestations of SSc include acute renal failure and hypertension (SRC), but also chronic renal impairment in up to half of SSc cases. Histological similarities of vasculopathy in SRC and PAH-SSc, evidence of upregulation of the ET-1 ligand-receptor axis in SRC, and our open label study confirming the safety of the non-selective ET-1 receptor antagonist (ERA) bosentan in SRC, make ET-1 receptor blockade a valid therapeutic approach. There is evidence of benefit from bosentan in SRC cases compared with a recent comparator cohort, with better renal function 3-12 months after SRC and worsening blood pressure control after stopping bosentan. We believe that a selective ERA that blocks the ETA, but not ETB, receptor subtype might be particularly advantageous in treating renal complications of SSc, because of potential adverse effects of ETB blockade that could worsen intra-renal vasoconstriction and cause renal sodium and water retention. We will test this hypothesis in a parallel group placebo controlled study of the highly selective ETA antagonist zibotentan in SSc with confirmed mild-to-moderate renal impairment, and also assess the safety and potential benefit of adding zibotentan to standard therapy in SRC. This study will address an important clinical question and help to elucidate key pathogenic mechanisms in the renal complications of SSc.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL;SKIN
Title: Treatment of urinary incontinence after stroke in adults
Funder: Department of Health and Social Care

Abstract: Urinary incontinence (UI) affects half of UK stroke survivors in the acute phase (47,450 people per annum, with 44% and 38% of stroke survivors remaining incontinent at 3 months and 1 year respectively (1). Currently, patients with UI after stroke typically receive care focused on containment strategies that do not promote continence (e.g. pads) and may be harmful (e.g. indwelling urethral catheters (2-4)). Improving the management of UI after stroke has been identified as an urgent priority in successive National Clinical Guidelines (5) and Sentinel Stroke National Audit Programme (SSNAP) reports (6) but there is little evidence care has improved. UI is a high priority for patients and their carers (2): it is distressing for individuals and families with depression twice as common in stroke survivors with UI (7). Negative social consequences for survivors and carers cannot be ignored: both may become isolated and marginalised (8). Two Patient, Carer and Public Involvement (PCPI) members from our ICONS: Identifying Continence OptioNs after Stroke programme will join the team contributing to tasks including forming recommendations and writing the plain language summary. We have identified 6 additional RCTs to date (2, 9-13) with 408 intervention and 238 control participants.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: RENAL AND UROGENITAL;STROKE