Research




Research

We are Bristol Renal, a world-renowned group researching glomerular disease.

In the last few years we have made great progress in understanding nephrotic syndrome, which is an umbrella term for a collection of symptoms that indicate kidney damage. We believe that 2018 was our best year yet, with major initiatives set in motion that could transform the way the disease is classified and managed, for the first time in decades.

Senior Personnel

Prof. Moin Saleem
Leading the team researching FSGS and nephrotic syndrome.

Dr Gavin Welsh
Non-clinical Reader, who is our senior scientist in the laboratory, and the key investigator for all the kidney disease projects ongoing in the Unit.

Prof. Richard Coward
Consultant paediatric nephrologist and MRC Senior Clinical Fellow. He is doing important work in the field of the nephrotic syndrome associated with diabetes – a huge and increasing problem, and the major cause of kidney failure worldwide

Dr Simon Satchell
University Reader and consultant nephrologist, and a key part of the team in Bristol working out the intricate details of how the filtration barrier of the kidney works.

Dr Becky Foster
Senior Lecturer who has developed world leading physiological ways of modelling kidney function, which are becoming a central part of the testing of patient samples.

The team continues to grow, and we currently have the following group of dedicated researchers working on Nephrotic Syndrome. In addition, we continue to train researchers from abroad, with recent visitors from Japan, India, South Africa and Egypt spending time in Bristol learning techniques and forging valuable international collaborations for the research

Recent Publications

https://jasn.asnjournals.org/content/early/2019/08/14/ASN.2018070729?fbclid=IwAR3GT94NNvBWuWVN_9PwUCbM3cxHtYZ86JjQO5diVV59Zx4dJWl5ehr14_007-02-19
Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways.

26-01-19
Effects of heparin and derivatives on podocytes: An in vitro functional and morphological evaluation.

00-01-19
Aldosterone induces albuminuria via matrix metalloproteinase–dependent damage of the endothelial glycocalyx

21-01-19
Renal Consequences of Therapeutic Interventions in Premature Neonates.

00-01-19
VEGFC reduces glomerular albumin permeability and protects against alterations in VEGF receptor expression in diabetic nephropathy.

00-01-19
Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function.

 

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NURTuRE

A particularly ambitious and exciting development is the birth of NURTuRE. This is a vision to create a national network of dedicated renal research nurses or study coordinators, based in (initially) the 14 busiest kidney units in the country. These   personnel are able to recruit patients (adults and children) to the RaDaR and NephroS studies in a systematic manner, which will catapult the size and depth of the cohort much beyond what has currently been possible. The network will be able to   benefit other renal disease cohorts as well as NS, therefore being able to collaboratively grow as the project progresses.

The project has considerable backing from pharmaceutical companies, in a way that clinicians/academics can contribute and benefit from industrial research and development, and vice versa.

Recruitment is well underway, and on target for completion of recruitment of the NS cohort by end of 2019. Additional dunding has been obtained for genetic sequencing of the cohort, as well as a major MRC ‘Stratified Medicine’ grant awarded to the NURTuRE team, led by Bristol. This grant is worth over £3M over 4 years, and has the ambitious aim of redefining NS through the detailed study of patient samples from NURTuRE, and therefore leading to the ability to target the correct new treatments to the correct patient, on an individual basis.

NURTuRE is overseen by a dedicated committee from the Renal Association and Kidney Research UK, who will govern how the information is kept safe, and used appropriately for research and patient benefit.

NephroS

NephroS is a national study where additional blood samples and DNA are collected from patients who are registered with RADAR, thus allowing for the first time highly detailed clinical and biological studies to be pursued on large numbers of patients in the UK. This nationwide data analysis is the most powerful way to gather new information on the disease and also permits the design of the highest quality clinical trials for new treatments in the future.

The study was initially open to sites (Hospitals) within the United Kingdom. There are approximately 38 sites in active recruitment in the UK; 20 of which are paediatric and 18 of which are adult sites. More and More sites are joining our efforts on a regular basis. 

We have now obtained substantial funding from the Medical Research Council to set up an ‘International NephroS’ cohort of patients. Data will be gathered in two large sites in India (Delhi and Bangalore), Sri Lanka and South Africa. This allows us both to boost numbers of patients substantially, for research and trials, and also to compare disease in different environments, which will give us important clues about the causes of nephrotic syndrome.

 

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Rare Disease Registry

The renal Rare Disease Registry (RADAR) has been developed by the Bristol team, as a national collaboration with all specialist renal units in the UK.

For the first time in the UK, we are recruiting all patients with Steroid Resistant Nephrotic Syndrome (SRNS - otherwise known as FSGS), and Steroid Sensitive Nephrotic Syndrome (SSNS), using RADAR as a centralised web-based database to compile nationwide data.

The website also allows patient/parent access, clinical information, discussion groups and access to the latest literature, via patients signing up to Renal Patient View. If you are a patient with FSGS/SRNS or SSNS, and are not yet registered on this database by your clinician, we encourage you to ask your renal physician to get you registered, via the website. Through RADAR, patients may either be recruited to NephroS, a well-established study with more than 1300 patient participants across the UK, or NURTuRE, our exciting new initiative. More information about these studies is available on the following page.

 

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What We Do

Genetic Research
An exciting development is the analysis of DNA from patients on the RADAR registry (see next page). As present we use Next Generation Sequencing (NGS), to analyse massive parts of the human genome for each patient, and identify important mutations or variations in the genetic code that will ultimately help to guide individual treatment options.

We now have funding under a government initiative to introduce this technology into the NHS, and also to enable whole genome sequencing of NS patients on RADAR. This will allow identification of any known genetic mutation causing the disease, as well as being a powerful research tool to discover new genes and variants that may cause the disease, or predict response to particular treatments. By building our expertise in ‘bioinformatics’ within the research team, we will have the ability to analyse these huge amounts of data for patients with NS.

Using genetic sequencing and bioinformatics skills, we have developed a 'Gene Panel' test for clinical use, which is approved for NHS use. This means that any patient with steroid resistant NS (SRNS) can now be tested by their clinician in a rapid manner not previously possible, by the Bristol Genetics Laboratories. A huge advance is that this test can check for all known genes in one simple blood test, something that would never have been possible using previous technology. We are also able to respond to new gene discoveries by adding those genes to the panel on a regular basis.

This work has been recognised by NHS England, and Bristol has just been announced as one of 2 specialist renal genetic testing centres for the whole of the UK.

Future Genetic Research Aims:

1. Continue to explore the huge amounts of information this gene sequencing technology yields, by analysing UK NS patients for subtle genetic modifications that may help to predict their response to steroids, or other immunosuppression, or their risk of kidney damage.

2. Undertake a new gene therapy project, whereby we will attempt to rescue certain inherited genetic kidney defects. Funded by Kidney Research UK.

3. Commence an exciting project that will explore the viability of a new chemical drug that can reverse disease in a particular type of genetic NS. This is being taken forward towards commercial development.

Plasma Research
This continues to be a large part of the research effort, in order to discover the 'factors' in circulating blood plasma that are responsible for causing a large proportion of Nephrotic Syndrome cases. The main aspects of the work are:

1. Establish the components in circulating blood plasma that cause damage to the podocyte cell. We have identified a group of proteins that cause specific effects on the podocyte, and are actively seeking and collecting plasma samples from patients with active disease in order to extend and validate these findings.

2. We are simultaneously looking at the effect of these plasma proteins on specific 'pathways' within the podocyte that become active in disease states. This would allow targeted therapies to be tried that can block the activity of these pathways, and thereby reverse the damage to the podocyte.

3. We have developed an active academic collaboration with an Industrial partner company, which allows us to test candidate compounds in a high throughput fashion, which can reverse the pathological effects we discover in podocytes.

Hundreds of patients have now been tested, not just from the UK but also worldwide, and the test continues to be improved in terms of speed and scope. Using the rare disease registry and the genetic analysis tools, we have discovered 5 new genes in the UK cohort of patients that cause steroid resistant NS, called CRB2, FAT1, ADCK4, MAGI2 and TBC1D8B. These new genes have been added to the clinical panel of genes that are tested for whenever a patient is diagnosed with SRNS.

 

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Nephrotic Syndrome

Nephrotic Syndrome may be considered as a collection of symptoms that indicate kidney damage.

Symptoms include:
• Albuminuria – Protein in the urine
• Hyperlipidaemia – High fat and cholesterol levels in the blood
• Oedema – Swelling, usually in the legs, feet or ankles
•Hypoalbuminemia – Low albumin levels in the blood

Within a kidney there are functional structures called nephrons, which consists of a glomerulus and an associated tubule. The glomerulus is essentially a ball of capillaries (fine blood vessels), and these are wrapped in cells known as podocytes.

Podocytes have foot projections that fit together with only narrow slits between them, and it is through these gaps that blood is filtered. These podocytes together with endothelial cells that line the inside of the capillaries are what makes up the glomerular filtration barrier. Podocytes are the cells targeted by diseases that lead to nephrotic syndrome, and therefore these symptoms occur because of a breakdown in the glomerular filtration barrier.

Bristol Renal

We receive fundraising and support from NeST, which underpins all of our activities. NeST helps us to kick-start important projects, and to gain that vital momentum that can then attract further funding from government and industrial bodies for the more ambitious projects. On a smaller scale this support is also used to fund projects undertaken by medical and science students, an important step in inspiring and training the next generation of researchers.

Patient involvement in research is vital to us, guiding our priorities, and inspiring us to do the best work possible to ultimately find a cure for this disease. We in the research team hugely enjoy our patient days in particular,
where we can interact with the most important people involved in the research, you!

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