The role of B cell inhibition in slowing progression of IgA nephropathy
IgA nephropathy is a frequent cause of end stage kidney disease, and the most common cause of primary glomerulonephritis worldwide. Effective therapies beyond antihypertensive treatments are not firmly established. IgA nephropathy is an autoimmune disorder driven by autoantibodies directed against poorly galactosylated IgA1, that deposit and cause progressive kidney damage. Our group are undertaking a wide range of clinical and laboratory studies in this condition.
This ACF is an opportunity to work on the BELIGA study, an experimental Phase 2 mechanistic trial, to study the effect of belimumab (B cell inhibition via anti-BAFF) in patients with IgA nephropathy. This study is funded through collaboration with GlaxoSmithKline, and ethical approval has been granted.
Using collected serum and urine samples, the successful ACF will investigate the effect of belimumab compared to placebo on B cell subsets and novel biomarkers in IgA nephropathy.
The ACF will benefit from:
- Training in a wide range of cutting-edge laboratory techniques
- Training in clinical trial conduct and experimental study set up
- Collaboration between academia and industry
Through this project, the ACF will be able to gain the training, skills and strong pilot data required for a funding application for a higher degree.
A mixed methods approach to evaluating the precipitants, pathobiological basis and multidimensional impact of loin pain in IgA nephropathy
A Kidney Research UK funded study: “Understanding and responding to the needs of patients with IgA nephropathy (IgAN)” identified that one of the major symptoms patients with IgAN complain of is intermittent loin pain. This is a completely unstudied area and this ACF/PhD will use a mixed methods approach to study the epidemiology, precipitants and pathobiological basis of loin (kidney) pain in IgAN. The ACF/PhD will comprise three components:
A nationwide survey of IgAN patients using the RaDaR registry (currently >3,000 patients) to quantitate the problem. Patient focus groups to evaluate the impact of pain on patient quality of life and begin to identify specific triggers.
A study of patients when in pain and when free of pain examining kidney architecture (MRI scan), serum, plasma and urine biomarker changes associated with kidney pain.
A feasibility study to determine whether it is possible to prospectively identify triggers of pain using SMART technology (mobile phone/apps/near patient testing) to record patient activity, monitor mood, environmental triggers, markers of infection as possible triggers.
During the ACF we would expect the trainee to collect pilot data to support a PhD proposal to cover definitive part 2 and 3 studies.
The role of complement in driving glomerular and tubulointerstitial injury in IgA nephropathy
With the advent of selective complement inhibitors and their introduction into the clinical arena it is now possible to selectively block the classical, alternative and lectin pathways. IgA nephropathy (IgAN) is the commonest pattern of glomerulonephritis in the world and outcome is heavily influenced by the extent of complement activation in the kidney that occurs following mesangial IgA deposition. It is therefore important that we understand which complement pathways are activated in individual patients and how they contribute to disease before we can personalise complement therapies to individual patients with IgAN (and other glomerular diseases). This ACF/PhD will combine both human and mechanistic animal studies.
Diagnostic kidney biopsies will be stained to specifically identify the relative activation of the two complement pathways known to be important in IgAN and link this to clinical outcome (Leicester IgAN biopsy archive: >800 biopsies with linked outcome data).
The relative importance of lectin and alternative pathway activation in driving glomerular and/or tubulointerstitial injury will be evaluated using an IgAN model in different transgenic mice deficient for specific components of the two complement systems.
During the ACF we would expect the trainee to collect pilot data to support a PhD proposal to support both parts of the study.
The role of the gut microbiome in determining the level of nephritogenic IgA immune complexes in IgA nephropathy
There is an increasing awareness of the importance of the gut microbiome in determining the development of many common diseases, including kidney disease. There is also extensive data to support a role for the gut associated lymphoid tissue in generating abnormal IgA responses in patients with IgA nephropathy (IgAN), and the hypothesis is that these responses are at least in part driven by the gut microbiota. This ACF/PhD will test this hypothesis by undertaking a Proof of Concept study to determine whether selective modulation of the gut microbiome alters circulating IgA responses in patients with IgAN.
Patients will be observed for 3 months, treated with a specific probiotic for 4 months and then followed up off treatment for a further 3 months off probiotic and serum, plasma, urine, faeces sequentially collected for evaluation of changes in faecal microbiota, circulating IgA phenotype and other biomarkers of interest.
The goal of this POC study will be to test whether altering the gut microbiome CAN alter circulating IgA immune responses in a way that could promote the progression of IgA nephropathy and therefore support a clinical trial of probiotic use in IgAN.
During the ACF we would expect the trainee to collect pilot data to support a PhD proposal to conduct this POC study.
A randomised controlled trial comparing the effectiveness and cost effectiveness of thrice weekly, extended, in-centre nocturnal haemodialysis versus standard care using a mixed methods approach
Haemodialysis can have extensive physiological, psychological and sociological impacts on patients. This is due to the side effects of haemodialysis and also the scheduling of treatment times, which results in patients ‘losing’ three days a week. Unsurprisingly, patient-reported quality of life is low, with many patients unable to continue paid employment. Home haemodialysis, including dialysis overnight at home, is one way of offering flexibility for patients but there are significant barriers for many. Alternatively, in-centre nocturnal dialysis offers patients the opportunity to dialyse overnight for longer while asleep. Despite growing evidence to support in-centre overnight dialysis, it remains underutilised due to both equipoise in the renal community and uncertainty from commissioners about the cost benefit of implementation. Leicester has just been awarded a £2.1m multi-centre grant to investigate this treatment option in more detail.
The ACF/PhD will run alongside a large, multi-centre clinical trial and involve:
- Working with the Leicester Clinical Trials Unit to understand the principles of trial management
- Learning qualitative research methods and assisting researchers in understanding the barriers and facilitators to implementing change within the NHS
- Assisting in an internal pilot study to understand the recruitment and retention to this interventional trial and subsequently working with the Clinical Trial Fellow on the interventional study.
- To work with our patient participation and involvement group in developing ways of engaging patients in research.
During the ACF we would expect the trainee to collect additional pilot data to support a PhD proposal to expand the remit of one of these work streams.
Daily intake of Lactobacillus casei Shirota (LcS) modulates intestinal permeability and decreases circulating levels of endotoxin that associate with cardiovascular mortality in haemodialysis patients
Haemodialysis (HD) patients have high rates of heart disease, hospitalisation and death. Inflammation is a common, non-traditional factor unique to dialysis patients and is strongly related to these poor clinical outcomes. There is increasing evidence that changes to intestinal permeability and the microbiome may play a role in this inflammation in HD patients. There are a number of unique factors related to the condition, the HD process, and dietary restrictions placed on this population that may cause these changes. Interventions that reduce such changes in HD patients are somewhat limited, however there is emerging evidence that the consumption of probiotics may be effective. A need for larger randomised controlled trials testing the efficacy of probiotic supplementation in HD patients has been recognised.
The ACF/PhD will run alongside an industry funded clinical trial and involve:
- Working with the Leicester Renal Research team to understand the principles of trial management
- Assisting experienced researchers to answer the following hypotheses:
- Twice daily intake of the pro-biotic Lactobacillus casei Shirota for six-months causes a reduction in circulating markers of cardiovascular disease risk
- Twice daily intake of the pro-biotic Lactobacillus casei Shirota for six-months is associated with improvements in markers of intestinal health and maintenance of the gut microbiome.
- Twice daily Lactobacillus casei Shirota is well tolerated and associated with improvements in clinical endpoints and quality of life
- Learning lab based skills with collaborators in Loughborough to measure circulating markers of systemic inflammation
During the ACF we would expect the trainee to collect additional pilot data to support a PhD proposal to for subsequent nutritional interventions in dialysis patients.
Urine exosome profiling in women who develop proteinuria in pregnancy
Development of proteinuria in pregnancy is multifactorial and can significantly impact maternal and fetal health. It may be isolate or be associated with high blood pressure (pre-eclampsia) or chronic kidney disease. Investigation of underlying cause is complicated in pregnancy by the relative difficulty of performing a renal biopsy and therefore diagnostic and prognostic biomarkers are needed to help risk stratify women and identify those at greatest risk of complications and most likely to benefit from intervention. The ACF/PhD will comprise three components:
Undertake a cross sectional study using urine from healthy pregnant women and pregnant women who develop proteinuria- purify the urine exosomes and perform next generation sequencing for mRNA and microRNA content and LC-MS/MS to identify associated proteins and identify exosomal mRNAs/miRs/proteins associated with proteinuria
Validate findings from the Part 1 biomarker discovery study with a second set of samples. Perform bioinformatic and laboratory analyses to determine potential cells of origin of the exosomes and biological function.
Undertake a prospective longitudinal study to examine changes in excretion of identified proteinuria-specific exosomal mRNA/miR/proteins during pregnancy in unselected cases and relate these to development of proteinuria, maternal and fetal outcomes.
During the ACF we would expect the trainee to collect pilot data to support a PhD proposal to cover definitive part 2 and 3 studies.
Determining the clinically relevant anatomy to teach UG medical students
Human anatomy has been a core component of undergraduate medical education for many years, and while it continues to be a key theme, the depth of anatomy taught has seen a steady decline. The need for a solid foundation of anatomical knowledge, while more readily appreciated as essential for those pursuing surgical careers, is important for any practicing clinician. Clearly, which areas of anatomy are most relevant will vary depending on the postgraduate speciality. With ever increasing pressures on space within the UG curriculum, there is obvious priority to ensuring what is taught best enables students to meet the demands of the breadth of future clinical practice.
While the GMC do not currently stipulate specific outcomes for the level of anatomy within the UG medical curriculum, the future introduction of the UK Medical Licensing Assessment will likely lead to efforts to better establish ILOs for the basic sciences, as a whole. In 2016, in response to the lack of consensus and guidance on the appropriate level of anatomy, the Anatomical Society defined a core regional anatomy syllabus of 156 ILOs, which were to help curriculum planners determine the clinically relevant anatomy to teach UG medical students. The proposed ILOs were determined by a Delphi panel of experts, which included surgeons, radiologists and anatomists.
The first step of the project will involve a series of focus groups and surveys with a variety of early clinical trainees from medicine, surgery and primary care. The purpose of this will be to identify whether there are elements of the 156 identified ILOs that represent a base of anatomical knowledge common across a breadth of specialities (surgical and non-surgical). The second step will be to explore how well they perceive (by self-report) to have retained knowledge of those areas of anatomy (identified in the first step of the project).
The findings from this project will help to better define areas of anatomy that are seen as most important, relevant and common to a breadth of clinical specialities. Further work/projects could explore how this anatomy could be prioritised or given greater attention within the UG medical curriculum, or early postgraduate period and whether there are any interventions that can be applied to improve retention of knowledge in those areas.